DCC-2036

DCC-2036 (Rebastinib) is a highly potent, non-ATP-competitive BCR-ABL1 inhibitor with IC50 of 0.8 and 4 nM for native ABL1 and gatekeeper mutant ABL1 T315I, respectively; also inhibits the SRC family kinases SRC, LYN, FGR, and HCK, and the receptor TKs KDR, FLT3, and TIE2 (IC50s=2-40 nM), but spares c-KIT (IC50=480 nM) ; potently inhibits unphosphorylated and phosphorylated of ABL1 native with IC50 of 0.75 and 2 nM, potently inhibits unphosphorylated and phosphorylated of ABL1 T315I with IC50 of 5 and 4 nM, also potently inhibits ABL1 H396P (IC50=1.4 nM) ; inhibits cellular proliferation of Ba/F3 cells expressing native or T315I mutant with IC50 of 5.4 and 13 nM, also inhibits proliferation of several common TKI-resistant mutants of BCR-ABL1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T with IC50 of 6-150 nM; prolongs survival in mouse Ba/F3 cell allograft models.Blood Cancer Phase 2 Clinical (In Vitro) :Rebastinib potently (IC50 0.82 nM) inhibits u-ABL1native, which is thought to exist predominantly in the inactive type II conformation. In addition, Rebastinib also strongly inhibits p-ABL1native (IC50 2 nM), which more readily adopts an active, Type I conformation.Rebastinib potently inhibits both u-ABL1T315I (IC50 5 nM) and p-ABL1T315I (IC50 4 nM), both of which exist predominately in the Type I conformation due to stabilization of an activating hydrophobic spine by the T315I mutation.In addition to ABL1, Rebastinib also inhibits the SRC family kinases LYN, SRC, FGR, and HCK, and PDGFRα, and PDGFRβ with IC50 of 29±1, 34±6, 38±1, 40±1, 70±10 and 113±10 nM, respectively. Notably, Rebastinib spared c-KIT (IC50 481 nM) .Rebastinib effectively inhibits the proliferation of Ba/F3 cells expressing native BCR-ABL1native (IC50 5.4 nM) . Rebastinib also inhibits proliferation of the Ph+ cell line K562 (IC50 5.5 nM) .Rebastinib also inhibits proliferation of several common TKI-resistant mutants of BCR-ABL1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T, at IC50s ranging from 6-150 nM. Rebastinib effectively inhibits autophosphorylation of BCR-ABL1native (IC50 29 nM) and BCR-ABL1T315I (IC50 18 nM), as well as the phosphorylation of STAT5 in both cell lines (IC50 28 nM and 13 nM, respectively) . (In Vivo) :A single dose of Rebastinib (DCC-2036; oral; 100 mg/kg) affords circulating plasma levels that exceeds 12 μM for up to 24 hours, and effectively inhibits BCR-ABL1 signaling for up to 8 hours in Ba/F3-BCR-ABL1T315I leukemia cells isolated from BM and spleen of tumor-bearing mice.Treatment of mice bearing Ba/F3-BCR-ABL1T315I leukemia cells with Rebastinib at 100 mg/kg once daily by oral gavage significantly prolonged their survival, while STI571 at 100 mg/kg twice daily is ineffective.In this aggressive allograft model, Rebastinib is as effective for treatment of BCR-ABLT315I leukemia as STI571 at 100 mg/kg twice daily in BCR-ABL1native leukemia, and reduces the leukemia cell burden in the spleens of treated mice.