Description
InformationRipretinib (DCC-2618) DCC-2618 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.TargetsPDGFR ; WT KIT (Cell-free assay); D816H KIT (Cell-free assay); V654A KIT (Cell-free assay); D816V KIT (Cell-free assay) 30587,; 4 nM; 5 nM; 8 nM; 14 nMIn vitroDCC-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 vivoDCC-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.Cell Research(from reference)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