HS-438, a new inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia.

Imatinib is a selective breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitor (TKI) that has significantly improved the prognosis of patients with chronic myeloid leukemia (CML). However, T315I gene mutations of the BCR-ABL kinase domain have been shown to confer resistance to imatinib. In the present study, we synthesized a novel BCR-ABL inhibitor, HS-438, and identified its anti-leukemic effects in vitro and in vivo. We found that HS-438 strongly inhibited the expression of BCR-ABL signaling pathways in wild-type BCR-ABL (BaF3/WT) cells as well as T315I-mutated BCR-ABL (BaF3/T315I) cells with resistance to imatinib. HS-438 induced cell cycle arrest, particularly during the G0/G1 cell cycle phase, and induced apoptosis. In BaF3/T315I xenograft models, HS-438 significantly delayed tumor growth, unlike imatinib. In summary, we suggest that HS-438 may be a novel drug candidate with the therapeutic potential to target BCR-ABL and overcome imatinib resistance in patients with CML.

Yun SM ，Jung KH ，Kim SJ ，Fang Z ，Son MK ，Yan HH ，Lee H ，Kim J ，Shin S ，Hong S ，Hong SS ... -  《-》

HS-543 induces apoptosis of Imatinib-resistant chronic myelogenous leukemia with T315I mutation.

Kim SJ ，Jung KH ，Yan HH ，Son MK ，Fang Z ，Ryu YL ，Lee H ，Lim JH ，Suh JK ，Kim J ，Lee S ，Hong S ，Hong SS ... -  《Oncotarget》

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 ... -  《-》

Triptolide inhibits Bcr-Abl transcription and induces apoptosis in STI571-resistant chronic myelogenous leukemia cells harboring T315I mutation.

Shi X ，Jin Y ，Cheng C ，Zhang H ，Zou W ，Zheng Q ，Lu Z ，Chen Q ，Lai Y ，Pan J ... -  《CLINICAL CANCER RESEARCH》

Cleavage of BCR-ABL transcripts at the T315I point mutation by DNAzyme promotes apoptotic cell death in imatinib-resistant BCR-ABL leukemic cells.

Kim JE ，Yoon S ，Choi BR ，Kim KP ，Cho YH ，Jung W ，Kim DW ，Oh S ，Kim DE ... -  《-》