Pralsetinib

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Identification

Summary

Pralsetinib is a RET receptor tyrosine kinase inhibitor for the treatment of metastatic RET-driven non-small cell lung cancer.

Brand Names

Gavreto

Generic Name

Pralsetinib

DrugBank Accession Number

DB15822

Background

Pralsetinib, similar to the previously approved selpercatinib, is a kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs) over other RTK classes.^3,5,9 Enhanced RET (Rearranged during transfection) oncogene expression is a hallmark of many cancers, including non-small cell lung cancer. Although multikinase inhibitors, including cabozantinib, ponatinib, sorafenib, sunitinib, and vandetanib, have shown efficacy in RET-driven cancers, their lack of specificity is generally associated with substantial toxicity.³ Pralsetinib (BLU-667) and selpercatinib (LOXO-292) represent the first generation of specific RET RTK inhibitors for the treatment of RET-driven cancers.^1,3,9

Although a phase 1/2 trial of pralsetinib termed ARROW (NCT03037385) is still ongoing, pralsetinib was granted accelerated FDA approval on September 4, 2020, for the treatment of metastatic RET-fusion positive non-small cell lung cancer. It is currently marketed under the brand name GAVRETO™ by Blueprint Medicines.⁹

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Pralsetinib (DB15822)

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Weight

Average: 533.612
Monoisotopic: 533.266299469

Chemical Formula

C₂₇H₃₂FN₉O₂

Synonyms

• Pralsetinib

External IDs

• BLU 667
• BLU-123244
• BLU-667
• BLU123244
• WHO 11004
• X-581238
• X581238

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Pharmacology

Indication

Pralsetinib is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) in adult patients who are confirmed to possess a rearranged during transfection (RET) gene fusion, as determined by an FDA approved test.⁹ It is also indicated in adult and pediatric patients 12 years of age and older for the treatment of advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and for whom radioactive iodine is not appropriate.¹³ The indication for advanced or metastatic RET fusion-positive thyroid cancer was approved under accelerated approval based on the overall response rate and duration of response, and continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.¹³

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Advanced ret-fusion non small cell lung cancer		••••••••••••	•••••	••• •••••••••• ••••••• •••• • ••• •••••••••	•••••••
Treatment of	Advanced ret-fusion thyroid cancer		••••••••••••	•••••• •••••••••	••••••••••• •••••••••••••••••• ••••••• •••••••• •••••••	•••••••
Treatment of	Metastatic ret-fusion non small cell lung cancer		••••••••••••	•••••		•••••••
Treatment of	Metastatic ret-fusion thyroid cancer		••••••••••••	•••••• •••••••••	••••••••••• •••••••••••••••••• ••••••• •••••••• •••••••	•••••••

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Pharmacodynamics

Pralsetinib exerts an anti-tumour effect through specific inhibition of the rearranged during transfection (RET) tyrosine kinase, including multiple distinct oncogenic RET fusions, mutated RET kinase domains harbouring gatekeeper mutations, and in RET kinases with a variety of activating single point mutations.^1,2,3,4,9 Due to pralsetinib's high selectivity for RET over other kinases, both in vitro and in vivo,⁵ pralsetinib has been described as having a better safety profile compared to previously used multi-kinase inhibitors.^1,2,3,4 Despite this, pralsetinib use may increase the risk of hypertension, hemorrhagic events, impaired wound healing, hepatotoxicity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.⁹

Mechanism of action

Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase containing extracellular, transmembrane, and intracellular domains whose activity is required for normal kidney and nervous system development.^6,3 Constitutive RET activation is achieved through chromosomal rearrangements producing 5' fusions of dimerizable domains to the 3' RET tyrosine kinase domain leading to constitutive dimerization and subsequent autophosphorylation; the most common fusions are KIF5B-RET and CCDC6-RET, although more than 35 genes have been reported to fuse with RET.^3,1,7 Constitutive activation leads to increased downstream signalling and is associated with tumour invasion, migration, and proliferation.²

Pralsetinib (formerly referred to as BLU-667) was developed through screening more than 10,000 agnostically designed kinase inhibitors followed by extensive chemical modification to improve its properties. Pralsetinib displays in vitro IC₅₀ values for both WT RET as well as several mutant forms, including CCDC6-RET, in the range of 0.3-0.4 nmol/L, and is 100-fold more selective for RET kinase over 96% of 371 kinases tested.⁵ It is this specific inhibition of RET kinase that is associated with anti-tumour activity and clinical benefit in patients.^5,8,9

Despite increased selectivity for RET over other kinases, pralsetinib has been reported to inhibit DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRb, and FGFR1-2 at clinically relevant concentrations. The significance of these findings remains uncertain.⁹

Target	Actions	Organism
AProto-oncogene tyrosine-protein kinase receptor Ret	inhibitor	Humans
UEpithelial discoidin domain-containing receptor 1	inhibitor	Humans
UNT-3 growth factor receptor	inhibitor	Humans
UReceptor-type tyrosine-protein kinase FLT3	inhibitor	Humans
UTyrosine-protein kinase JAK1	inhibitor	Humans
UTyrosine-protein kinase JAK2	inhibitor	Humans
UHigh affinity nerve growth factor receptor	inhibitor	Humans
UVascular endothelial growth factor receptor 2	inhibitor	Humans
UPlatelet-derived growth factor receptor beta	inhibitor	Humans
UFibroblast growth factor receptor 1	inhibitor	Humans
UFibroblast growth factor receptor 2	inhibitor	Humans

Absorption

Pralsetinib given at 400 mg once daily resulted in a mean steady-state C_max of 2830 ng/mL (coefficient of variation, CV, 52.5%) and AUC_0-24h of 43900 ng*h/mL (CV 60.2%). The C_max and AUC of pralsetinib increased inconsistently with increasing doses between 60 and 600 mg once daily, with a median T_max across this range of between two and four hours. At 400 mg once daily, pralsetinib reached steady-state plasma concentration by three to five days.⁹

Pralsetinib absorption is affected by food. A single dose of 400 mg given with a high-fat meal (800 to 1000 calories with 50 to 60% of calories coming from fat) increased the mean C_max by 104% (95% CI 65-153%), mean AUC_0-∞ by 122% (95% CI 96-152%), and the median T_max from four to 8.5 hours.⁹

Volume of distribution

Pralsetinib has a mean apparent volume of distribution of 228 L (CV 75%).⁹

Protein binding

Pralsetinib is 97.1% bound to plasma proteins regardless of concentration.⁹

Metabolism

Pralsetinib is metabolized in vitro primarily by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Pralsetinib given as a single oral dose of 310 mg in healthy volunteers led to the detection of metabolites from both oxidation (M453, M531, and M549b) and glucuronidation (M709), although these constituted less than 5% of the detected material.⁹

Route of elimination

Pralsetinib is primarily eliminated through the fecal route (73%, 66% unchanged) with a small amount found in the urine (6%, 4.8% unchanged).⁹

Half-life

Pralsetinib has a plasma elimination half-life of 14.7 ± 6.5 hours following a single dose and 22.2 ± 13.5 hours following multiple doses.⁹

Clearance

Pralsetinib has a mean apparent steady-state oral clearance of 9.1 L/h (CV 60%).⁹

Adverse Effects

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Toxicity

Pralsetinib administered to rats at 20 mg/kg (roughly 2.5-3.6 times the recommended human exposure) resulted in resorption of litters in pregnant female mice in 92% of pregnancies (82% complete resorption); resorption occurred at doses as low as 5 mg/kg (0.3 times the recommended human exposure). Both male and female rats given 10 mg/kg pralsetinib or more had observable degeneration within the testis/ovaries. In 28-day rat and monkey studies, once-daily pralsetinib resulted in histological necrosis at doses 1.1 or more times the recommended human dose and myocardial hemorrhage at doses 2.6 or more times the recommended human dose. Also, pralsetinib induced hyperphosphatemia (rats only, dose 2.4-3.5 times the recommended human dose) and multi-organ mineralization (dose 0.11 or more times the recommended human dose).⁹

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Pralsetinib can be increased when it is combined with Abametapir.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Pralsetinib.
Abrocitinib	The serum concentration of Pralsetinib can be increased when it is combined with Abrocitinib.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Pralsetinib.
Acamprosate	The excretion of Acamprosate can be decreased when combined with Pralsetinib.

Food Interactions

• Take on an empty stomach. Food affects the absorption of pralsetinib. Patients should take pralsetinib either at least one hour before or at least two hours after a meal.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Gavreto	Capsule	100 mg	Oral	Blueprint Medicines (Netherlands) B.V.	2022-01-17	Not applicable
Gavreto	Capsule	100 mg/1	Oral	Rigel Pharmaceuticals, Inc.	2024-06-24	Not applicable
Gavreto	Capsule	100 mg/1	Oral	Blueprint Medicines Corporation	2020-09-04	2022-04-30
Gavreto	Capsule	100 mg	Oral	Blueprint Medicines (Netherlands) B.V.	2022-01-17	Not applicable
Gavreto	Capsule	100 mg	Oral	Hoffmann La Roche	2021-11-12	Not applicable

Categories

ATC Codes

L01EX23 — Pralsetinib

• L01EX — Other protein kinase inhibitors
• L01E — PROTEIN KINASE INHIBITORS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• BSEP/ABCB11 Inhibitors
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (strength unknown)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (strength unknown)
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Inducers
• Cytochrome P-450 CYP3A5 Inducers (strength unknown)
• Cytochrome P-450 CYP3A5 Inhibitors
• Cytochrome P-450 CYP3A5 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Kinase Inhibitor
• MATE 1 Inhibitors
• MATE 2 Inhibitors
• MATE inhibitors
• OAT1/SLC22A6 inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• Protein Kinase Inhibitors
• Rearranged during Transfection (RET) Inhibitors

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

1WPE73O1WV

CAS number

2097132-94-8

InChI Key

GBLBJPZSROAGMF-RWYJCYHVSA-N

InChI

InChI=1S/C27H32FN9O2/c1-16-11-22(33-23-12-17(2)35-36-23)34-25(31-16)19-7-9-27(39-4,10-8-19)26(38)32-18(3)20-5-6-24(29-13-20)37-15-21(28)14-30-37/h5-6,11-15,18-19H,7-10H2,1-4H3,(H,32,38)(H2,31,33,34,35,36)/t18-,19-,27+/m0/s1

IUPAC Name

(1s,4s)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide

SMILES

CO[C@@]1(CC[C@@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[C@@H](C)C1=CC=C(N=C1)N1C=C(F)C=N1

References

Synthesis Reference

Jason D. Brubaker, Joseph L. Kim, Kevin J. Wilson, Douglas Wilson, Lucian V. DiPietro, "Inhibitors of ret." U.S. Patent US20170121312A1, issued July 24, 2018.

General References

1. Russo A, Lopes AR, McCusker MG, Garrigues SG, Ricciardi GR, Arensmeyer KE, Scilla KA, Mehra R, Rolfo C: New Targets in Lung Cancer (Excluding EGFR, ALK, ROS1). Curr Oncol Rep. 2020 Apr 16;22(5):48. doi: 10.1007/s11912-020-00909-8. [Article]
2. Li AY, McCusker MG, Russo A, Scilla KA, Gittens A, Arensmeyer K, Mehra R, Adamo V, Rolfo C: RET fusions in solid tumors. Cancer Treat Rev. 2019 Dec;81:101911. doi: 10.1016/j.ctrv.2019.101911. Epub 2019 Oct 30. [Article]
3. Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F: State-of-the-Art Strategies for Targeting RET-Dependent Cancers. J Clin Oncol. 2020 Apr 10;38(11):1209-1221. doi: 10.1200/JCO.19.02551. Epub 2020 Feb 21. [Article]
4. Stinchcombe TE: Current management of RET rearranged non-small cell lung cancer. Ther Adv Med Oncol. 2020 Jul 26;12:1758835920928634. doi: 10.1177/1758835920928634. eCollection 2020. [Article]
5. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP, Wilson D, Wilson KJ, DiPietro L, Fleming P, Palmer M, Hu MI, Wirth L, Brose MS, Ou SI, Taylor M, Garralda E, Miller S, Wolf B, Lengauer C, Guzi T, Evans EK: Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov. 2018 Jul;8(7):836-849. doi: 10.1158/2159-8290.CD-18-0338. Epub 2018 Apr 15. [Article]
6. Takahashi M, Ritz J, Cooper GM: Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985 Sep;42(2):581-8. doi: 10.1016/0092-8674(85)90115-1. [Article]
7. Qian Y, Chai S, Liang Z, Wang Y, Zhou Y, Xu X, Zhang C, Zhang M, Si J, Huang F, Huang Z, Hong W, Wang K: KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer. Mol Cancer. 2014 Jul 21;13:176. doi: 10.1186/1476-4598-13-176. [Article]
8. Piotrowska Z, Isozaki H, Lennerz JK, Gainor JF, Lennes IT, Zhu VW, Marcoux N, Banwait MK, Digumarthy SR, Su W, Yoda S, Riley AK, Nangia V, Lin JJ, Nagy RJ, Lanman RB, Dias-Santagata D, Mino-Kenudson M, Iafrate AJ, Heist RS, Shaw AT, Evans EK, Clifford C, Ou SI, Wolf B, Hata AN, Sequist LV: Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion. Cancer Discov. 2018 Dec;8(12):1529-1539. doi: 10.1158/2159-8290.CD-18-1022. Epub 2018 Sep 26. [Article]
9. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
10. Pralsetinib product sheet [Link]
11. Roche News Release: Gavreto for the treatment of NSCLC [Link]
12. FDA Approved Drug Products: GAVRETO (pralsetinib) capsules, for oral use (July 2023) [Link]
13. FDA Approved Drug Products: GAVRETO (pralsetinib) capsules, for oral use (August 2023) [Link]

External Links

ChemSpider

75533827

RxNav

2394936

ChEMBL

CHEMBL4582651

PDBe Ligand

Q4J

Wikipedia

Pralsetinib

PDB Entries

7du9 / 7ju5

Clinical Trials

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not Available	Approved for Marketing	Not Available	Non-Small Cell Lung Cancer (NSCLC) / Thyroid Gland Medullary Carcinoma	1	somestatus	stop reason	just information to hide
Not Available	Recruiting	Not Available	Advanced Solid Tumors / Metastatic Cancer / Solid Tumors	1	somestatus	stop reason	just information to hide
3	Active Not Recruiting	Treatment	Adenocarcinomas / Bronchial Diseases / Bronchogenic Carcinoma / Carcinoma / Head and Neck Neoplasms / Lung Disorder / Lung Neoplasm / Neoplasm / Neoplasms by Histologic Type / Neoplasms by Site / Neoplasms, Embryonal Germ Cell Tumors / Neoplasms, Nerve Tissue / Non-Small Cell Lung Carcinoma / Respiratory Tract Diseases / Respiratory Tract Neoplasms / RET-fusion Non Small Cell Lung Cancer / Thoracic Neoplasms	1	somestatus	stop reason	just information to hide
3	Withdrawn	Treatment	Thyroid Gland Medullary Carcinoma	1	somestatus	stop reason	just information to hide
2	Active Not Recruiting	Treatment	Breast Cancer / Gastrointestinal Tract Cancer / Non-Small Cell Lung Cancer (NSCLC) / Other Cancers	1	somestatus	stop reason	just information to hide

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Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	100 mg/1
Capsule	Oral	100 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US10030005	No	2018-07-24	2036-11-01
US11273160	No	2019-04-03	2039-04-03
US11872192	No	2019-04-03	2039-04-03
US11963958	No	2019-04-03	2039-04-03

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	<0.1 mg/ml	Pralsetinib product sheet

Predicted Properties

Property	Value	Source
logP	3.65	Chemaxon
pKa (Strongest Acidic)	12.45	Chemaxon
pKa (Strongest Basic)	4.13	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	8	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	135.53 Å2	Chemaxon
Rotatable Bond Count	8	Chemaxon
Refractivity	146.12 m3·mol-1	Chemaxon
Polarizability	56.66 Å3	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-001i-0002090000-2154411131d142800b8f
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udi-0112390000-ab4bcd61afe14005fc4a
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0900-9661210000-85af00e6538de4a2a290
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udi-0589270000-7549d223055fd1f4caa0
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0gca-4220790000-5cc66defd27c0c655d02
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-001u-1490210000-84f647420a188a9e5a02

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Proto-oncogene tyrosine-protein kinase receptor Ret

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Inhibition of mutant RET kinase activity is thought to be the main mechanism of action for pralsetinib.

General Function

Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15) (PubMed:20064382, PubMed:20616503, PubMed:20702524, PubMed:21357690, PubMed:21454698, PubMed:24560924, PubMed:28846097, PubMed:28846099, PubMed:28953886, PubMed:31118272). In contrast to most receptor tyrosine kinases, RET requires not only its cognate ligands but also coreceptors, for activation (PubMed:21994944, PubMed:23333276, PubMed:28846097, PubMed:28846099, PubMed:28953886). GDNF ligands (GDNF, NRTN, ARTN, PSPN and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways (PubMed:21994944, PubMed:23333276, PubMed:24560924, PubMed:25242331, PubMed:28846097, PubMed:28846099, PubMed:28953886). Acts as a dependence receptor via the GDNF-GFRA1 signaling: in the presence of the ligand GDNF in somatotrophs within pituitary, promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF (PubMed:20616503, PubMed:21994944). Required for the molecular mechanisms orchestration during intestine organogenesis via the ARTN-GFRA3 signaling: involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue (By similarity). Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses (PubMed:28846097, PubMed:28846099, PubMed:28953886). Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner (PubMed:20702524, PubMed:21357690). Also active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage (PubMed:21357690). Triggers the differentiation of rapidly adapting (RA) mechanoreceptors (PubMed:20064382). Involved in the development of the neural crest (By similarity). Regulates nociceptor survival and size (By similarity). Phosphorylates PTK2/FAK1 (PubMed:21454698)

Specific Function

Atp binding

Gene Name

RET

Uniprot ID

P07949

Uniprot Name

Proto-oncogene tyrosine-protein kinase receptor Ret

Molecular Weight

124317.465 Da

References

1. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP, Wilson D, Wilson KJ, DiPietro L, Fleming P, Palmer M, Hu MI, Wirth L, Brose MS, Ou SI, Taylor M, Garralda E, Miller S, Wolf B, Lengauer C, Guzi T, Evans EK: Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov. 2018 Jul;8(7):836-849. doi: 10.1158/2159-8290.CD-18-0338. Epub 2018 Apr 15. [Article]
2. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
3. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details2. Epithelial discoidin domain-containing receptor 1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Tyrosine kinase that functions as a cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11

Specific Function

Atp binding

Gene Name

DDR1

Uniprot ID

Q08345

Uniprot Name

Epithelial discoidin domain-containing receptor 1

Molecular Weight

101126.72 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details3. NT-3 growth factor receptor

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation

Specific Function

Atp binding

Gene Name

NTRK3

Uniprot ID

Q16288

Uniprot Name

NT-3 growth factor receptor

Molecular Weight

94427.47 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details4. Receptor-type tyrosine-protein kinase FLT3

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways

Specific Function

Atp binding

Gene Name

FLT3

Uniprot ID

P36888

Uniprot Name

Receptor-type tyrosine-protein kinase FLT3

Molecular Weight

112902.51 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details5. Tyrosine-protein kinase JAK1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway (PubMed:16239216, PubMed:28111307, PubMed:32750333, PubMed:7615558, PubMed:8232552). Kinase partner for the interleukin (IL)-2 receptor (PubMed:11909529) as well as interleukin (IL)-10 receptor (PubMed:12133952). Kinase partner for the type I interferon receptor IFNAR2 (PubMed:16239216, PubMed:28111307, PubMed:32750333, PubMed:7615558, PubMed:8232552). In response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins (PubMed:7759950). Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors (PubMed:16239216, PubMed:32750333, PubMed:8232552)

Specific Function

Atp binding

Gene Name

JAK1

Uniprot ID

P23458

Uniprot Name

Tyrosine-protein kinase JAK1

Molecular Weight

133275.995 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details6. Tyrosine-protein kinase JAK2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:7615558, PubMed:9657743, PubMed:15690087). Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:9618263, PubMed:15690087). Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain (PubMed:9657743). Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430). Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214). Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980)

Specific Function

Acetylcholine receptor binding

Gene Name

JAK2

Uniprot ID

O60674

Uniprot Name

Tyrosine-protein kinase JAK2

Molecular Weight

130672.475 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details7. High affinity nerve growth factor receptor

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1281417, PubMed:15488758, PubMed:17196528, PubMed:1849459, PubMed:1850821, PubMed:22649032, PubMed:27445338, PubMed:8325889). Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors

Specific Function

Atp binding

Gene Name

NTRK1

Uniprot ID

P04629

Uniprot Name

High affinity nerve growth factor receptor

Molecular Weight

87496.465 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details8. Vascular endothelial growth factor receptor 2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC

Specific Function

Atp binding

Gene Name

KDR

Uniprot ID

P35968

Uniprot Name

Vascular endothelial growth factor receptor 2

Molecular Weight

151525.555 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details9. Platelet-derived growth factor receptor beta

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Tyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor

Specific Function

Atp binding

Gene Name

PDGFRB

Uniprot ID

P09619

Uniprot Name

Platelet-derived growth factor receptor beta

Molecular Weight

123966.895 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details10. Fibroblast growth factor receptor 1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation

Specific Function

Atp binding

Gene Name

FGFR1

Uniprot ID

P11362

Uniprot Name

Fibroblast growth factor receptor 1

Molecular Weight

91866.935 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Details11. Fibroblast growth factor receptor 2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

Pralsetinib is selective for RET over other kinases; detectable inhibition of other kinases at clinically achievable concentrations has been observed but the significance of this inhibition remains unknown.

General Function

Protein tyrosine kinase activity

Specific Function

Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosi...

Gene Name

FGFR2

Uniprot ID

P21802

Uniprot Name

Fibroblast growth factor receptor 2

Molecular Weight

92024.29 Da

References

1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

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Drug created at September 10, 2020 13:51 / Updated at December 05, 2023 12:31