Home Protein Tyrosine Kinase c-Kit inhibitor Ripretinib

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Ripretinib c-Kit inhibitor

Cat.No.S8757

Ripretinib is an orally bioavailable switch pocket control inhibitor of wild-type and mutated forms of the tumor-associated antigens (TAA) mast/stem cell factor receptor (SCFR) Kit (c-Kit) and PDGFR-alpha, with IC50 values of 4 nM, 8 nM, 18 nM, 5 nM and 14 nM for WT Kit (c-Kit), V654A Kit (c-Kit), T670I Kit (c-Kit), D816H Kit (c-Kit) and D816V Kit (c-Kit), respectively.
Ripretinib c-Kit inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 510.36

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Quality Control

Batch: Purity: 99.82%
99.82

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (557 to 558 residues) and A829P mutant and Y823D mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.003 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (557 to 558 residues) and N822K mutant and Y823D mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.004 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (557 to 558 residues) mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.004 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (557 to 558 residues) and D820A mutant and D820A mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.006 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (557 to 558 residues) and D816H mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.013 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (557 to 558 residues) and Y823D mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.014 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit V560D mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.023 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (557 to 558 residues) and V654A mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.031 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 9 AY502 to 503 insertion mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.034 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit D816V mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.037 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (557 to 558 residues) and D816H mutant and T670I mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.037 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of TEL-fused PDGFRalpha (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.04 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of TEL-fused PDGFRbeta (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.045 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit V560D/D816H mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.048 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit V560D/V654A mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.075 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 9 AY502 to 503 insertion and D816 mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.078 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of KDR (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.098 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 11 deletion (560 to 578 residues) mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.13 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of PDGFRalpha V561D/D842V mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.188 μM. 30204441
Growth inhibition assay BA/F3 72 hrs Inhibition of Kit exon 9 AY502 to 503 insertion and V654 mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50 = 0.205 μM. 30204441
Cytotoxicity assay BA/F3 72 hrs Cytotoxicity in mouse parental BA/F3 cells incubated for 72 hrs by MTS assay, GI50 = 8.037 μM. 30204441
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Solubility

In vitro
Batch:

DMSO : 100 mg/mL (195.94 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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Mass Concentration Volume Molecular Weight
Dilution Calculator Molecular Weight Calculator

In vivo
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In vivo Formulation Calculator (Clear solution)

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Chemical Information, Storage & Stability

Molecular Weight 510.36 Formula

C24H21BrFN5O2

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 1442472-39-0 -- Storage of Stock Solutions

Synonyms DCC-2618 Smiles CCN1C2=CC(=NC=C2C=C(C1=O)C3=CC(=C(C=C3Br)F)NC(=O)NC4=CC=CC=C4)NC

Mechanism of Action

Targets/IC50/Ki
PDGFR
WT KIT
(Cell-free assay)
4 nM
D816H KIT
(Cell-free assay)
5 nM
V654A KIT
(Cell-free assay)
8 nM
D816V KIT
(Cell-free assay)
14 nM
T670I KIT
(Cell-free assay)
18 nM
In vitro

DCC-2618 is a switch-control type II inhibitor of KIT, which arrests KIT in an inactive state, regardless of activating mutations, such as KIT D816V. In CHO cells transiently transfected with both single and double (primary/secondary) KIT mutants, DCC-2618 robustly inhibits exon 17, exon 9/13, exon 9/14, and exon 9/17 KIT mutants, as well as exon 11/17 KIT mutants, including exon 17 D816V, D816G, D820A, D820E, D820Y, N822K, N822Y, N822H, and Y823D primary or secondary mutations. DCC-2618 inhibits the proliferation and survival of various human mast cell lines (HMC-1, ROSA, MCPV-1) as well as primary neoplastic mast cells obtained from patients with advanced systemic mastocytosis (IC50 <1 μM). DCC-2618 decreases growth and survival of primary neoplastic eosinophils obtained from patients with systemic mastocytosis or eosinophilic leukemia, leukemic monocytes obtained from patients with chronic myelomonocytic leukemia with or without concomitant systemic mastocytosis, and blast cells obtained from patients with acute myeloid leukemia. Furthermore, DCC-2618 suppresses the proliferation of endothelial cells and may have additional drug effects on systemic mastocytosis-related angiogenesis. DCC-2618 downregulates IgE-mediated histamine release from basophils and tryptase release from mast cells.
In vivo

In vivo, DCC-2618 administration at 50 mg/kg affords an ED90 for inhibition of KIT phosphorylation in the GIST T1 xenograft model, corresponding to an EC90 concentration of ∼ 470 ng/mL. When give twice daily, this oral dose results in almost complete tumor stasis. This dose of DCC-2618 produces tumor regressions in a patient derived xenograft (PDX) GIST expressing KIT exon 11 delW557K558/exon 17 Y823D, and also in a KIT exon 17 N822K AML xenograft model. In xenograft studies, DCC-2618 blocks KIT and PDGFRA-driven tumor growth, including of KIT exon 17 mutants found in GIST (Y823D), AML (N822K), and mastocytosis (D816V) models.
References

Applications

Methods Biomarkers Images PMID
Western blot KIT / BTK STAT5 / AKT / ERK
S8757-WB-1
29439183

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT05080621 Withdrawn
Gastrointestinal Stromal Tumors
Deciphera Pharmaceuticals LLC
 November 2021 Phase 1|Phase 2
NCT04633122 Completed
Gastrointestinal Stromal Tumor(GIST)
Zai Lab (Shanghai) Co. Ltd.|Zai Lab (Hong Kong) Ltd.
 November 25 2020 Phase 2
NCT02571036 Completed
Gastrointestinal Stromal Tumors|Advanced Systemic Mastocytosis|Advanced Cancers
Deciphera Pharmaceuticals LLC
 November 2015 Phase 1

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