Identification

Name
Pralsetinib
Accession Number
DB15822
Description

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
Thumb
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

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

Pralsetinib is currently approved for this indication under an accelerated approval scheme and continued approval may be contingent on future confirmatory trials.9

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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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

TargetActionsOrganism
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 Cmax of 2830 ng/mL (coefficient of variation, CV, 52.5%) and AUC0-24h of 43900 ng*h/mL (CV 60.2%). The Cmax and AUC of pralsetinib increased inconsistently with increasing doses between 60 and 600 mg once daily, with a median Tmax 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 Cmax by 104% (95% CI 65-153%), mean AUC0-∞ by 122% (95% CI 96-152%), and the median Tmax 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
Learn about our commercial Adverse Effects data.
Learn More
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

Affected organisms
  • Humans and other mammals
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.
DrugInteraction
AbametapirThe serum concentration of Pralsetinib can be increased when it is combined with Abametapir.
AbemaciclibThe excretion of Pralsetinib can be decreased when combined with Abemaciclib.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Pralsetinib.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Pralsetinib.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Pralsetinib.
AcetohexamideThe metabolism of Acetohexamide can be decreased when combined with Pralsetinib.
Acetylsalicylic acidThe metabolism of Acetylsalicylic acid can be decreased when combined with Pralsetinib.
AcyclovirThe excretion of Acyclovir can be decreased when combined with Pralsetinib.
Adefovir dipivoxilThe excretion of Adefovir dipivoxil can be decreased when combined with Pralsetinib.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Pralsetinib.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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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

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
GavretoCapsule100 mg/1OralBlueprint Medicines Corporation2020-09-04Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Classification
Not classified

Chemical Identifiers

UNII
1WPE73O1WV
CAS number
2097132-94-8
InChI Key
GBLBJPZSROAGMF-BATDWUPUSA-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
SMILES
CO[[email protected]]1(CC[[email protected]@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[[email protected]@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. [PubMed:32296961]
  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. [PubMed:31715421]
  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. [PubMed:32083997]
  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. [PubMed:32782485]
  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. [PubMed:29657135]
  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. [PubMed:2992805]
  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. [PubMed:25047660]
  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. [PubMed:30257958]
  9. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
  10. Pralsetinib product sheet [Link]
ChemSpider
71060332
ChEMBL
CHEMBL4297597
Wikipedia
Pralsetinib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentAdenocarcinomas / Bronchial Diseases / Carcinoma NOS / Carcinoma, Bronchogenic / Chronic Lung Diseases / Neoplasms / Neoplasms by Histologic Type / Neoplasms by Site / Neoplasms, Germ Cell and Embryonal / Neoplasms, Head and Neck / Neoplasms, Lung / Neoplasms, Nerve Tissue / Non-Small Cell Lung Carcinoma (NSCLC) / Respiratory Tract Diseases / Respiratory Tract Neoplasms / RET-fusion Non Small Cell Lung Cancer / Thoracic Neoplasms1
1, 2RecruitingTreatmentAdenocarcinoma, Papillary / Adenocarcinomas / Carcinoma NOS / Carcinoma, Bronchogenic / Chronic Lung Diseases / Colonic Diseases / Colonic Neoplasms / Digestive System Diseases / Digestive System Neoplasms / Endocrine Gland Neoplasms / Endocrine System Diseases / Gastrointestinal Diseases / Intestinal Diseases / Intestinal Neoplasms / Medullary Thyroid Cancer (MTC) / Neoplasm, Bronchial / Neoplasms / Neoplasms by Histologic Type / Neoplasms by Site / Neoplasms, Colorectal / Neoplasms, Gastrointestinal / Neoplasms, Germ Cell and Embryonal / Neoplasms, Glandular and Epithelial / Neoplasms, Head and Neck / Neoplasms, Lung / Neoplasms, Nerve Tissue / Neoplasms, Thyroid / Neuroectodermal Tumors / Neuroendocrine Carcinomas / Neuroendocrine Tumors / Non-Small Cell Lung Carcinoma (NSCLC) / Respiratory Tract Diseases / Respiratory Tract Neoplasms / RET-altered Colon Cancer / RET-altered Non Small Cell Lung Cancer / RET-altered Papillary Thyroid Cancer / RET-altered Solid Tumors / Thoracic Neoplasms / Thyroid Cancer, Papillary / Thyroid Diseases1
Not AvailableAvailableNot AvailableMedullary Thyroid Cancer (MTC) / Non-Small Cell Lung Carcinoma (NSCLC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral100 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<0.1 mg/mlPralsetinib product sheet
Predicted Properties
PropertyValueSource
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell de...
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. [PubMed:29657135]
  2. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
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
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, dif...
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]
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]
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
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
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]
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
Ubiquitin protein ligase binding
Specific Function
Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
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]
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
Sh2 domain binding
Specific 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 adaptiv...
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]
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
Transmembrane receptor protein tyrosine kinase activity
Specific 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 sympatheti...
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]
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
Vascular endothelial growth factor-activated receptor activity
Specific 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 ...
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]
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
Vascular endothelial growth factor binding
Specific Function
Tyrosine-protein kinase that acts as 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...
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]
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 embryonic development, cell proliferation, differentiation ...
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]
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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Flockhart Table of Drug Interactions [Link]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  3. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. FDA Approved Drug Products: GAVRETO (pralsetinib) oral capsules [Link]

Drug created on September 10, 2020 07:51 / Updated on September 12, 2020 21:35

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