ON012380

ON012380 is a kinase inhibitor with an IC₅₀ of 9 nM against BCR-ABL. As a substrate-competitive BCR-ABL inhibitor, ON012380 binds to a non-ATP site, and inhibits the kinase activities of PDGFR, Fyn and LynB at higher concentrations. ON012380 induces apoptosis, inhibits STAT-5 phosphorylation, reduces cell viability and suppresses cell growth in leukemia cells. ON012380 can be used in the research of chronic myeloid leukemia and Imatinib (HY-15463)-resistant chronic myeloid leukemia^[1][2][3][4]. In Vitro:ON012380 (1 nM-1 μM; 30 min pre-incubation, 20 min kinase reaction) potently inhibits wild-type BCR-ABL kinase activity with an IC₅₀ of 9.0 nM, and acts synergistically with Imatinib (HY-15463) to reduce the IC₅₀ to 0.83 nM^[1].
ON012380 (0.1 nM-1000 nM; 30 min pre-incubation, 20 min kinase reaction) acts as a substrate-competitive inhibitor of wild-type BCR-ABL, with IC₅₀ values unaffected by ATP concentration but increased by higher Crk substrate concentrations^[1].
ON012380 (30 min pre-incubation, 20 min kinase reaction) potently inhibits the kinase activity of the Imatinib-resistant BCR-ABL^T315I mutant with an IC₅₀ of 1.5 nM^[1].
ON012380 (72 h) reduces viability of K562 and 32Dcl3-p210BCR-ABL cells with an LD₅₀ of 10-15 nM^[1].
ON012380 (10 nM-1000 nM; 24 h) dose-dependently inhibits BCR-ABL kinase activity and suppresses STAT-5 phosphorylation in K562 cells^[1].
ON012380 (72 h) reduces viability of all tested Imatinib-resistant BCR-ABL mutant-expressing 32Dcl3 cell lines with LD₅₀ values ranging from 5.9 nM to 10.0 nM^[1].
ON012380 (1 nM-1000 nM; 24 h) dose-dependently inhibits BCR-ABL^T315I kinase activity and suppresses STAT-5 phosphorylation in 32Dcl3-BCR-ABL^T315I cells^[1].
ON012380 potently inhibits growth of cells expressing wild-type Bcr-Abl and all tested Imatinib-resistant Bcr-Abl mutants (including BCR-ABL^T315I) at concentrations < 10 nM, and also inhibits PDGFR- and Lyn-dependent cell proliferation with an IC₅₀ of approximately 80 nM^[2].
ON012380 (1.38-9 nM) potently inhibits wild-type Bcr-Abl kinase activity with an IC₅₀ of 9 nM and the Imatinib-resistant Bcr-Abl^T315I mutant with an IC₅₀ of 1.38 nM via non-ATP competitive binding^[3].
ON012380 (<10 nM) induces apoptosis and cell death in Ph+ CML cells expressing the Imatinib-resistant BCR-ABL^T315I isoform^[3].
ON012380 (2-24 h) reduces viability and induces apoptosis in IL-3-dependent BaF3 cells, wild-type BCR-ABL-transformed BaF3 cells, and BCR-ABL^T315I-mutant BCR-ABL-transformed BaF3 cells, with no significant inhibition of BCR-ABL signaling (Stat5 and CrkL phosphorylation)^[4].
ON012380 reduces viability with an IC₅₀ of ~300 nM and induces apoptosis in K562, BV-173, and T315I-mutant BCR-ABL-expressing BV-173R CML cells, but has limited activity in Lyn-overexpressing K562R cells, with no associated inhibition of BCR-ABL or Lyn kinase signaling^[4]. In Vivo:ON012380 (100 mg/kg; i.p.; daily) reduces circulating Imatinib-resistant BCR-ABL^T315I leukemic cells in athymic nude mice with a favorable safety profile^[1].
ON012380 (100 mg/kg; i.p.; daily; 21 days) produces significant growth inhibition of Bcr-Abl^T315I-positive leukemias in nude mice without causing hematoxicity^[3].
ON012380 (200 mg/kg; i.v.; single dose) does not impair normal hematopoietic colony formation in CD-1 mice^[1].