DCC-2618 is an orally active, potent type II switch pocket (SP) inhibitor against c-KIT (IC50 = 4 nM/WT, 8 nM/V654A, 18 nM/T670I, 5 nM/D816H, 14 nM/D816V) and PDGFR. DCC-2618 locks c-KIT & PDGFR in an inactive conformation and is effective against multiple clinical forms of mutations resistant to type I ATP (catalytic)-site inhibitors Imatinib and Sunitinib. DCC-2618 inhibits cellular c-KIT activation (IC50 = 36 nM/WT, 2 nM/ex 11 del, 7 nM/ex 11 del & V654A, 53 nM/V560D & D820A) and is efficacious against KIT mutants-mediated cancer growth in cultres (IC50 = 2 nM; GIST with KIT D816Y) and in mice in vivo (50 mg/kg b.i.d. p.o.; GIST with KIT delW557K558/Y823D, AML with KIT N822K).
Orally active, potent type II switch pocket (SP) c-KIT & PDGFR inhibitor against multiple clinical forms of mutations resistant to Imatinib and Sunitinib.
Systemic mastocytosis is a complex disease defined by abnormal growth and accumulation of neoplastic mast cells in various organs. Most patients exhibit a D816V-mutated variant of KIT, which confers resistance against imatinib. Clinical problems in systemic mastocytosis arise from mediator-related
Tyrosine kinase inhibitors may initially control gastrointestinal stromal tumors, but most patients eventually experience disease progression due to activation loop mutations, which are resistant to approved drugs. However, phase I trials suggest that the cancer is sensitive to two new
DCC-2618, a pan KIT and PDGFR switch control inhibitor, achieves proof-of-concept in a first-in-human study
Janku F, George S, Razak A, Gordon M, Brooks D, Flynn DG, Kaufman M, Pitman J, Smith B, et al
European Journal of Cancer, 69, S4 (suppl-S4 (suppl (2016)
DCC-2618 is a potent inhibitor of wild-type and mutant KIT, including refractory Exon 17 D816 KIT mutations, and exhibits efficacy in refractory GIST and AML xenograft models, [abstract]
Smith BD, Hood MM, Wise SC, Kaufman MD, Lu WP, Rutkoski T, Flynn DL, Heinrich MC.
Cancer Research, 75 (15 Suppl), Abstract nr 2690-Abstract nr 2690 (2015)
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