DCC-2036 is an ABL switch control inhibitor with IC50 of 0.8 and 2 nM for u-ABL1native and p-ABL1native, respectively. DCC-2036 strongly prevents both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 suppresses BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia. In addition, DCC-2036 also inhibits other kinases with IC50 of 2,4,6,34,29 and 38 nM for Flt3, KDR, Tie2, Src, LYN and FGR kinases, respectively. [1][2][3] |
