DCC-2036 is a conformational controlBcr-Abl inhibitor for Abl1 (WT) and Abl1 (T315I) with IC50 of 0.8 nM and 4 nM, also inhibits SRC, LYN, FGR, HCK, KDR, FLT3, and Tie-2.
Bcr-Abl is a constitutively active tyrosine kinase that drives survival and proliferation through multiple downstream pathways[3]. DCC-2036 is a Bcr-Abl inhibitor for Abl1WT, Abl1T315I and Abl1H396P with IC50 values of 0.8 nM, 4 nM and 1.4 nM, respectively[1]. In vitro, DCC-2036 effectively inhibited proliferation of the Ba/F3 cells expressing Bcr-Abl1WT with IC50 values of 5.4 nM, but DCC-2036 also retained potency against Ba/F3 cells expressing Bcr-Abl1 mutants that was resistant to imatinib, dasatinib, and nilotinib. DCC-2-35 also inhibited proliferation of the Ba/F3 cells expressing Bcr-Abl1T315I and the Ph+ cell line K562 with IC50 values of 13 nM and 5.5 nM, respectively. In addition, DCC-2036 inhibited proliferation of several common TKI-resistant mutants of Bcr- Abl1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T, at IC50 values ranging from 6 – 150 nM. DCC-2036 effectively inhibited autophosphorylation of Bcr-Abl1WT and Bcr-Abl1T315I with IC50 values of 29 nM and 18 nM, respectively, as well as the phosphorylation of STAT5 in Ba/F3 cells expressing Bcr-Abl1WT or Bcr-Abl1T315I with IC50 values of 28 nM and 13 nM, respectively. In vivo, a single oral dose of DCC-2036 at 100 mg/kg afforded circulating plasma levels that exceeded 12 μM for up to 24 hour, and effectively inhibited Bcr-Abl1 signaling for up to 8 hours in Ba/F3-Bcr-Abl1T315I leukemia cells isolated from bone marrow and spleen of tumor-bearing mice, as assessed by intracellular flow cytometric staining for phospho-STAT5. Oral administration of DCC-2036 at 100 mg/kg twice daily significantly prolonged the survival of the mice bearing Ba/F3- Bcr-Abl1T315I leukemia cells and reduced the leukemia cell burden in the spleens. Oral administration of DCC-2036 at doses of 60 - 100 mg/kg/d prolonged survival and reduced circulating leukemia cells in physiologically relevant mouse models of CML-like myeloproliferative neoplasia and Ph+ B-cell acute lymphoblastic leukemia induced by Bcr-Abl1T315I[1].
作用机制
DCC-2036 potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation[1].
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