Name | Ripretinib |
Synonyms | DCC-2618 DCC2618 DCC 2618 Ripretinib RIPRETINIB Ripretinib (DCC-2618) N-[4-Bromo-5-[1-ethyl-1,2-dihydro-7-(methylamino)-2-oxo-1,6-naphthyridin-3-yl]-2-fluorophenyl]-N'-phenylurea |
CAS | 1442472-39-0 |
Molecular Formula | C24H21BrFN5O2 |
Molar Mass | 510.36 |
Density | 1.544±0.06 g/cm3(Predicted) |
Boling Point | 568.6±50.0 °C(Predicted) |
pKa | 12.15±0.70(Predicted) |
Storage Condition | Room Temprature |
Physical and Chemical Properties | Bioactive DCC-2618 is a Kit (c-Kit) and PDGFR-alpha inhibitor with oral activity. The IC50 for WT Kit (c-Kit), V654A Kit (c-Kit), T670I Kit (c-Kit), D816H Kit (c-Kit) and D816V Kit (c-Kit) are 4 nM, 8 nM, 18 nM, 5 nM and 14 nM respectively. |
Use | Application KIT/PDGFR INHIBITOR(DCC-2618) is an investigational oral kinase conversion control inhibitor currently under development for the treatment of gastrointestinal stromal tumors (GIST), advanced systemic mastocytosis (ASM), gliomas and other solid tumors (KIT) or platelet-derived growth factor alpha (PDGFRα) kinases driven by the tyrosine protein kinase KIT (where genetic mutations or alterations of these kinases play a key role in the biology of these tumors that lead to drug resistance and disease progression). Deciphera focused the development of the KIT/PDGFR INHIBITOR(DCC-2618) on a subgroup of patients with serious unmet medical needs despite currently available treatments. |
In vitro study | DCC-2618 efficiently and broadly inhibit primary and drug-resistant mutants of KIT, such as mutations occurring in exons 9, 11, 13, 14, 17, and 18, and in exons 12, 14, 14 of PDGFRA, 18 primary mutations. DCC-2618 inhibition of multiple properties of KIT at nanomolar levels of potency: WT (IC50 4 nM), V654A (8 nM), T670I (18 nM), D816H (5 nM), d816V (14 nM). In CHO cells Transiently transfected with primary and secondary mutants of KIT, DCC-2618 inhibited Exon 17, Exon 9/13, Exon 9/14, Exon 9/17, KIT for exon 11/17 mutations, including D816V, D816G, D820A, D820E, D820Y, N822K, N822Y, N822H, and Y823D primary or secondary mutations located in Exon 17. In the MO7e cell line, phosphorylation of wild-type KIT was inhibited by DCC-2618 (IC50=36 nM). In human GIST cell lines, including GIST T1 (deletion exon 11), GIST 430 (deletion exon 11/exon 13 V654A) and GIST 48 (exon 11 V560D/d817 exon 20A), DCC-2618 can also effectively inhibit the activation of KIT. In mouse mastocytosis, DCC-2618 can effectively inhibit the proliferation of P815 cells (expressing Exon 17 D816Y mutation KIT) with IC50 of 2 nM. Proliferation and survival were inhibited by HMC-1 in a variety of human mast cell lines (MCPV-1, ROSA, DCC-2618) and in primary tumor mast cells isolated from patients with advanced systemic mastocytosis. |
In vivo study | In vivo, 50 mg/kg DCC-2618 inhibited KIT phosphorylation in the GIST T1 xenograft model to 90% of the effective dose (ED90) with an EC50 of approximately 470 ng/mL. Two times daily oral administration, DCC-2618 can almost completely cause tumor stasis. In a xenograft model, DCC-2618 prevented KIT and PFGFRA-driven tumor growth. |