Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML).

As the critical driving force for chronic myeloid leukemia (CML), BCR gene fused ABL kinase has been extensively explored as a validated target of drug discovery. Although imatinib has achieved tremendous success as the first-line treatment for CML, the long-term application ultimately leads to resistance, primarily via various acquired mutations occurring in the BCR-ABL kinase. Although dasatinib and nilotinib have been approved as second-line therapies that could overcome some of these mutants, the most prevalent gatekeeper T315I mutant remains unconquered. Here, we report a novel type II kinase inhibitor, CHMFL-48, that potently inhibits the wild-type BCR-ABL (wt) kinase as well as a panel of imatinib-resistant mutants, including T315I, F317L, E255K, Y253F, and M351T. CHMFL-48 displayed great inhibitory activity against ABL wt (IC50: 1 nM, 70-fold better than imatinib) and the ABL T315I mutant (IC50: 0.8 nM, over 10,000-fold better than imatinib) in a biochemical assay and potently blocked the autophosphorylation of BCR-ABL wt and BCR-ABL mutants in a cellular context, which further affected downstream signalling mediators, including signal transducer and activator of transcription 5 (STAT5) and CRK like proto-oncogene (CRKL), and led to the cell cycle progression blockage as well as apoptosis induction. CHMFL-48 also exhibited great anti-leukemic efficacies in vivo in K562 cells and p210-T315I-transformed BaF3 cell-inoculated murine models. This discovery extended the pharmacological diversity of BCR-ABL kinase inhibitors and provided more potential options for anti-CML therapies.

Lu T ，Cao J ，Zou F ，Li X ，Wang A ，Wang W ，Liang H ，Liu Q ，Hu C ，Chen C ，Hu Z ，Wang W ，Li L ，Ge J ，Shen Y ，Ren T ，Liu J ，Xia R ，Liu Q ... -  《-》

PBA2, a novel inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia.

Chronic Myeloid Leukemia (CML) is largely caused by the Philadelphia (Ph) chromosome carrying the Break point Cluster Region-Abelson (BCR-ABL) oncogene. Imatinib is a BCR-ABL-targeted therapy and considered the standard of care in CML management. Resistance to imatinib therapy often develops because of mutations in the BCR-ABL kinase domain. In this study, we evaluated PBA2, a novel BCR-ABL inhibitor, for its anti-cancer activity against BCR-ABL expressing BaF3 cells. PBA2 shows potent activity against wild-type and T315I mutated BaF3 cells as compared with imatinib. PBA2 inhibited the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. PBA2 inhibited the mRNA expression of BCR-ABL in BaF3/WT and BaF3/T315I cells. Mechanistically, PBA2 increased the cell population in sub G1 phase of the cell cycle, induced apoptosis and elevated ROS production in both BaF3/WT and BaF3/T315I cells. Taken together, our results indicate that PBA2 exhibits anti-proliferative effects and inhibits the imatinib-resistant T315I BCR-ABL mutation. PBA2 may be a novel drug candidate for overcoming the resistance to imatinib in CML patients.

Gupta P ，Kathawala RJ ，Wei L ，Wang F ，Wang X ，Druker BJ ，Fu LW ，Chen ZS ... -  《-》

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro.

Wu LX ，Wu Y ，Chen RJ ，Liu Y ，Huang LS ，Lou LG ，Zheng ZH ，Chen YZ ，Xu JH ... -  《-》

Discovery and characterization of a novel highly potent and selective type II native and drug-resistant V299L mutant BCR-ABL inhibitor (CHMFL-ABL-039) for Chronic Myeloid Leukemia (CML).

Wu J ，Wang A ，Li X ，Chen C ，Qi Z ，Hu C ，Wang W ，Wu H ，Huang T ，Zhao M ，Wang W ，Hu Z ，Liu Q ，Wang B ，Wang L ，Li L ，Ge J ，Ren T ，Xia R ，Liu J ，Liu Q ... -  《-》

Anthelmintic niclosamide suppresses transcription of BCR-ABL fusion oncogene via disabling Sp1 and induces apoptosis in imatinib-resistant CML cells harboring T315I mutant.

Jin B ，Wang C ，Shen Y ，Pan J ... -  《Cell Death & Disease》