Ripretinib

Identification

Summary

Ripretinib is a kinase inhibitor used to treat advanced gastrointestinal stromal tumor (GIST).

Brand Names

Qinlock

Generic Name

Ripretinib

DrugBank Accession Number

DB14840

Background

Ripretinib is a kinase inhibitor used for the treatment of advanced gastrointestinal stromal tumor (GIST) that has not adequately responded to other kinase inhibitors such as sunitinib and imatinib. Ripretinib, also known as Qinlock, is manufactured by Deciphera Pharmaceuticals and was initially approved by the FDA on May 15, 2020.⁷

It is the first drug approved as a fourth-line therapy in the specific setting of prior treatment with a minimum of 3 other kinase inhibitors.⁸

Type

Small Molecule

Groups

Approved

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Ripretinib (DB14840)

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Weight

Average: 510.367
Monoisotopic: 509.086266

Chemical Formula

C₂₄H₂₁BrFN₅O₂

Synonyms

• Ripretinib

External IDs

• DCC-2618

Pharmacology

Indication

Ripretinib is indicated to treat adults diagnosed with advanced gastrointestinal stromal tumor (GIST) who have had prior therapy with at least 3 kinase inhibitors, including the imatinib.⁷

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Associated Conditions

• Advanced Gastrointestinal Stromal Tumor (GIST)

Contraindications & Blackbox Warnings

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Pharmacodynamics

As a broad-spectrum kinase inhibitor, ripretinib inhibits various gene mutations, increasing progression-free survival in patients with advanced gastrointestinal stromal tumors (GIST).^10,11 It is effective in treating mutations that are resistant to chemotherapy with other kinase inhibitors, such as imatinib.⁷

Ripretinib has the propensity to cause cardiac dysfunction and new primary cutaneous malignancy. It is important to measure cardiac ejection fraction before and during treatment as well as to perform regular dermatological assessments.⁷

Mechanism of action

Protein kinases play important roles in cellular function, and their dysregulation can lead to carcinogenesis.⁴ Ripretinib inhibits protein kinases including wild type and mutant platelet-derived growth factor receptor A (PDGFRA) and KIT that cause the majority of gastrointestinal stromal tumor (GIST).⁵ In vitro, ripretinib has been shown to inhibit PDGFRB, BRAF, VEGF, and TIE2 genes.^2,3,7

Ripretinib binds to KIT and PDGFRA receptors with mutations on the exons 9, 11, 13, 14, 17 and 18 (for KIT mutations), and exons 12, 14 and 18 (for PDGFRA mutations).¹ The “switch pocket” of a protein kinase is normally bound to the activation loop, acting as an “on-off switch” of a kinase. Ripretinib boasts a unique dual mechanism of action of binding to the kinase switch pocket as well as the activation loop, thereby turning off the kinase and its ability to cause dysregulated cell growth.^1,9

Target	Actions	Organism
AMast/stem cell growth factor receptor Kit	inhibitor	Humans
APlatelet-derived growth factor receptor beta	inhibitor	Humans
AAngiopoietin-1 receptor	inhibitor	Humans
AVascular endothelial growth factor receptor 2	inhibitor	Humans
ASerine/threonine-protein kinase B-raf	inhibitor	Humans
APlatelet-derived growth factor receptor alpha	inhibitor	Humans

Absorption

Ripretinib is absorbed in the gastrointestinal tract and Tmax is achieved in 4 hours, with steady-state concentrations reached within 14 days.⁷

Volume of distribution

The mean volume of distribution of ripretinib is 307 L.⁷

Protein binding

Ripretinib is over 99% bound to albumin and alpha-1 acid glycoprotein. ⁷

Metabolism

Ripretinib is metabolized by the CYP3A subfamily of enzymes with contributions from CYP2D6 and CYP2E1 to its active metabolite, DP-5439.⁷

Hover over products below to view reaction partners

• Ripretinib
  • DP-5439

Route of elimination

Ripretinib is 34% excreted in the feces and 0.2% excreted in the urine.⁷

Half-life

The average half-life of ripretinib is 14.8 hours.⁷

Clearance

The mean apparent clearance of ripretinib is 15.3 L/hour.⁷

Adverse Effects

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Toxicity

There is limited information in the literature regarding an overdose with ripretinib, and LD50 information is not readily available.⁷ Like other kinase inhibitors, an overdose with ripretinib likely results in hematological toxicity, skin toxicity, as well as muscle, liver, and gastrointestinal toxicity.^6,7

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 Ripretinib can be increased when it is combined with Abametapir.
Abemaciclib	The serum concentration of Ripretinib can be increased when it is combined with Abemaciclib.
Acyclovir	The excretion of Acyclovir can be decreased when combined with Ripretinib.
Afatinib	The serum concentration of Ripretinib can be increased when it is combined with Afatinib.
Alectinib	Alectinib may decrease the excretion rate of Ripretinib which could result in a higher serum level.
Allopurinol	Ripretinib may decrease the excretion rate of Allopurinol which could result in a higher serum level.
Alpelisib	The serum concentration of Alpelisib can be increased when it is combined with Ripretinib.
Ambrisentan	The serum concentration of Ambrisentan can be increased when it is combined with Ripretinib.
Amiodarone	The serum concentration of Ripretinib can be increased when it is combined with Amiodarone.
Apalutamide	The serum concentration of Ripretinib can be decreased when it is combined with Apalutamide.

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Food Interactions

• Take with or without food.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Qinlock	Tablet	50 mg	Oral	Deciphera Pharmaceuticals. Llc	2020-12-10	Not applicable
Qinlock	Tablet	50 mg/1	Oral	Deciphera Pharmaceuticals, LLC	2020-05-15	Not applicable

Categories

Drug Categories

• Antineoplastic Agents
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP2E1 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• MATE 1 Inhibitors
• MATE inhibitors
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• Protein Kinase Inhibitors

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

9XW757O13D

CAS number

1442472-39-0

InChI Key

CEFJVGZHQAGLHS-UHFFFAOYSA-N

InChI

InChI=1S/C24H21BrFN5O2/c1-3-31-21-12-22(27-2)28-13-14(21)9-17(23(31)32)16-10-20(19(26)11-18(16)25)30-24(33)29-15-7-5-4-6-8-15/h4-13H,3H2,1-2H3,(H,27,28)(H2,29,30,33)

IUPAC Name

1-{4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl}-3-phenylurea

SMILES

CCN1C(=O)C(=CC2=C1C=C(NC)N=C2)C1=C(Br)C=C(F)C(NC(=O)NC2=CC=CC=C2)=C1

References

General References

1. Nemunaitis J, Bauer S, Blay JY, Choucair K, Gelderblom H, George S, Schoffski P, Mehren MV, Zalcberg J, Achour H, Ruiz-Soto R, Heinrich MC: Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Future Oncol. 2020 Jan;16(1):4251-4264. doi: 10.2217/fon-2019-0633. Epub 2019 Nov 22. [Article]
2. Mazzocca A, Napolitano A, Silletta M, Spalato Ceruso M, Santini D, Tonini G, Vincenzi B: New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv Med Oncol. 2019 May 17;11:1758835919841946. doi: 10.1177/1758835919841946. eCollection 2019. [Article]
3. Villanueva MT: Ripretinib turns off the switch in GIST. Nat Rev Drug Discov. 2019 Jul;18(7):499. doi: 10.1038/d41573-019-00099-4. [Article]
4. Kannaiyan R, Mahadevan D: A comprehensive review of protein kinase inhibitors for cancer therapy. Expert Rev Anticancer Ther. 2018 Dec;18(12):1249-1270. doi: 10.1080/14737140.2018.1527688. Epub 2018 Oct 9. [Article]
5. Liu P, Tan F, Liu H, Li B, Lei T, Zhao X: The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor. Onco Targets Ther. 2020 Mar 24;13:2433-2447. doi: 10.2147/OTT.S241331. eCollection 2020. [Article]
6. Kozuki T: Skin problems and EGFR-tyrosine kinase inhibitor. Jpn J Clin Oncol. 2016 Apr;46(4):291-8. doi: 10.1093/jjco/hyv207. Epub 2016 Jan 29. [Article]
7. FDA Approved Drug Products: QINLOCK (ripretinib) tablets, for oral use [Link]
8. FDA Approves First Drug for Fourth-Line Treatment of Advanced Gastrointestinal Stromal Tumors [Link]
9. GIST Support International: Switch Pocket Kinase Inhibitors [Link]
10. Deciphera phase 1 study results [Link]
11. Deciphera phase 3 study results [Link]

External Links

ChemSpider

67886378

RxNav

2369389

ChEMBL

CHEMBL4216467

Wikipedia

Ripretinib

AHFS Codes

• 10:00.00 — Antineoplastic Agents

FDA label

Download (817 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Gastrointestinal Stromal Tumors	2
2	Active Not Recruiting	Treatment	Gastrointestinal Stromal Tumors	1
2	Recruiting	Treatment	Gastrointestinal Stromal Tumor(GIST)	1
1	Active Not Recruiting	Treatment	Advanced Cancers / Advanced Systemic Mastocytosis / Gastrointestinal Stromal Tumors	1
1	Recruiting	Treatment	GIST - Gastrointestinal Stromal Tumor	1
Not Available	Approved for Marketing	Not Available	GIST - Gastrointestinal Stromal Tumor	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	50 mg
Tablet	Oral	50 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8940756	No	2012-06-07	2032-06-07
US8461179	No	2012-06-07	2032-06-07
US8188113	No	2010-07-27	2030-07-27

Properties

State

Solid

Experimental Properties

Property	Value	Source
boiling point (°C)	568.6±50.0	http://www.chemspider.com/Chemical-Structure.67886378.html
logP	5.63	https://www.chemsrc.com/en/cas/1225278-16-9_525350.html
pKa	12.10	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62627748.htm

Predicted Properties

Property	Value	Source
Water Solubility	0.00583 mg/mL	ALOGPS
logP	4.3	ALOGPS
logP	4.39	ChemAxon
logS	-4.9	ALOGPS
pKa (Strongest Acidic)	10.34	ChemAxon
pKa (Strongest Basic)	5.85	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	4	ChemAxon
Hydrogen Donor Count	3	ChemAxon
Polar Surface Area	86.36 Å2	ChemAxon
Rotatable Bond Count	5	ChemAxon
Refractivity	133.78 m3·mol-1	ChemAxon
Polarizability	47.21 Å3	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Mast/stem cell growth factor receptor Kit

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Transmembrane receptor protein tyrosine kinase activity

Specific Function

Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell main...

Gene Name

KIT

Uniprot ID

P10721

Uniprot Name

Mast/stem cell growth factor receptor Kit

Molecular Weight

109863.655 Da

References

1. Nemunaitis J, Bauer S, Blay JY, Choucair K, Gelderblom H, George S, Schoffski P, Mehren MV, Zalcberg J, Achour H, Ruiz-Soto R, Heinrich MC: Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Future Oncol. 2020 Jan;16(1):4251-4264. doi: 10.2217/fon-2019-0633. Epub 2019 Nov 22. [Article]
2. Liu P, Tan F, Liu H, Li B, Lei T, Zhao X: The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor. Onco Targets Ther. 2020 Mar 24;13:2433-2447. doi: 10.2147/OTT.S241331. eCollection 2020. [Article]
3. FDA Approved Drug Products: QINLOCK (ripretinib) tablets, for oral use [Link]

Details2. Platelet-derived growth factor receptor beta

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Supported by in vitro studies only.

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. Nemunaitis J, Bauer S, Blay JY, Choucair K, Gelderblom H, George S, Schoffski P, Mehren MV, Zalcberg J, Achour H, Ruiz-Soto R, Heinrich MC: Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Future Oncol. 2020 Jan;16(1):4251-4264. doi: 10.2217/fon-2019-0633. Epub 2019 Nov 22. [Article]
2. FDA Approved Drug Products: QINLOCK (ripretinib) tablets, for oral use [Link]

Details3. Angiopoietin-1 receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Supported by Supported by in vitro studies only.

General Function

Transmembrane receptor protein tyrosine kinase activity

Specific Function

Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading...

Gene Name

TEK

Uniprot ID

Q02763

Uniprot Name

Angiopoietin-1 receptor

Molecular Weight

125829.005 Da

References

1. FDA Approved Drug Products: QINLOCK (ripretinib) tablets, for oral use [Link]

Details4. Vascular endothelial growth factor receptor 2

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Supported by in vitro studies only.

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: QINLOCK (ripretinib) tablets, for oral use [Link]

Details5. Serine/threonine-protein kinase B-raf

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Supported by in vitro studies only.

General Function

Protein serine/threonine kinase activity

Specific Function

Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, a...

Gene Name

BRAF

Uniprot ID

P15056

Uniprot Name

Serine/threonine-protein kinase B-raf

Molecular Weight

84436.135 Da

References

1. FDA Approved Drug Products: QINLOCK (ripretinib) tablets, for oral use [Link]

Details6. Platelet-derived growth factor receptor alpha

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Vascular endothelial growth factor-activated receptor activity

Specific Function

Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chem...

Gene Name

PDGFRA

Uniprot ID

P16234

Uniprot Name

Platelet-derived growth factor receptor alpha

Molecular Weight

122668.46 Da

References

1. Villanueva MT: Ripretinib turns off the switch in GIST. Nat Rev Drug Discov. 2019 Jul;18(7):499. doi: 10.1038/d41573-019-00099-4. [Article]
2. Mazzocca A, Napolitano A, Silletta M, Spalato Ceruso M, Santini D, Tonini G, Vincenzi B: New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv Med Oncol. 2019 May 17;11:1758835919841946. doi: 10.1177/1758835919841946. eCollection 2019. [Article]
3. FDA Approved Drug Products: QINLOCK (ripretinib) tablets, for oral use [Link]

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Drug created on May 20, 2019 14:29 / Updated on May 14, 2021 11:41