Ripretinib

Catalog No.S8757 Batch:S875701

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Technical Data

Formula

C24H21BrFN5O2
Molecular Weight 510.36 CAS No. 1442472-39-0
Solubility (25°C)* In vitro DMSO 100 mg/mL (195.94 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description 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.
Targets
PDGFR [2] WT KIT [1]
(Cell-free assay)		 D816H KIT [1]
(Cell-free assay)		 V654A KIT [1]
(Cell-free assay)		 D816V KIT [1]
(Cell-free assay)		 View More
4 nM 5 nM 8 nM 14 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[1]. 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[2].
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[1]. 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[3].

Protocol (from reference)

Cell Assay:

[2]
  • Cell lines

    HMC-1.1, HMC-1.2, ROSA (KIT WT) and ROSA (KIT D816V) cells

  • Concentrations

    0.5-5 μM

  • Incubation Time

    4 h

  • Method

    For evaluation of KIT and BTK signaling, HMC-1.1, HMC-1.2, ROSA (KIT WT) and ROSA (KIT D816V) cells are incubated in control medium or in DCC-2618 (0.5–5 μM) for 4 h at 37°C. Western blotting is performed.
Animal Study:

[3]
  • Animal Models

    xenograft models (mice)

  • Dosages

    100 mg/kg/day or 25 mg/kg/day or 50 mg/kg BID

  • Administration

    oral

Selleck's Ripretinib has been cited by 7 publications

CRISPR/Cas9-engineering of HMC-1.2 cells renders a human mast cell line with a single D816V-KIT mutation: An improved preclinical model for research on mastocytosis [ Front Immunol, 2023, 14:1078958] PubMed: 37025992
Chinese Pedigree with Hereditary Gastrointestinal Stromal Tumors: A Case Report and Literature Review [ Int J Mol Sci, 2023, 24(1)830] PubMed: 36614290
Inhibition of human UDP-glucuronosyltransferase enzyme by ripretinib: Implications for drug-drug interactions [ Toxicol Appl Pharmacol, 2023, 466:116490] PubMed: 36963523
Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension [ Immunity, 2022, S1074-7613(22)00291-6] PubMed: 35863346
Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor [ Cancers (Basel), 2021, 13(15)3699] PubMed: 34359600
A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity [ J Pers Med, 2020, 10(4)E234] PubMed: 33212994
An evaluation of masitinib for treating systemic mastocytosis [ Expert Opin Pharmacother, 2019, 20(13):1539-1550] PubMed: 31381378

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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