2. Academic Validation
  3. Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia

Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia

  • Cancer Lett. 2020 Mar 1;472:132-141. doi: 10.1016/j.canlet.2019.11.040.
Pranav Gupta 1,  Guan-Nan Zhang 1,  Anna Maria Barbuti 1,  Xin Zhang 2,  Nishant Karadkhelkar 1,  Jingfeng Zhou 3,  Ke Ding 2,  Jingxuan Pan 3,  Sabesan Yoganathan 1,  Dong-Hua Yang 4,  Zhe-Sheng Chen 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
  • 2 School of Pharmacy, Jinan University, Guangzhou, 510632, China.
  • 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA. Electronic address: yangd1@stjohns.edu.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA. Electronic address: chenz@stjohns.edu.
PMID: 31837444 DOI: 10.1016/j.canlet.2019.11.040
Abstract

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm primarily due to the presence of the Bcr-Abl fusion gene that produces the constitutively active protein, Bcr-Abl. Imatinib, a BCR-ABL-targeted drug, is a first-line drug for the treatment of CML. Resistance to imatinib occurs as a result of mutations in the Bcr-Abl kinase domains. In this study, we evaluated S116836, a novel Bcr-Abl Inhibitor, for its anti-cancer efficacy in the wild-type (WT) and T315I mutant Bcr-Abl. S116836 was efficacious in BaF3 cells with WT or T315I mutated Bcr-Abl genotypes. S116836 inhibits the phosphorylation of Bcr-Abl and its downstream signaling in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 arrests the cells in the G0/G1 phase of cell cycle, induces Apoptosis, increases ROS production, and decreases GSH production in BaF3/WT and BaF3/T315I cells. Moreover, in mouse tumor xenografts, S116836 significantly inhibits the growth and volume of tumors expressing the WT or T315I mutant Bcr-Abl without causing significant cardiotoxicity. Overall, our results indicate that S116836 significantly inhibits the imatinib-resistant T315I Bcr-Abl mutation and could be a novel drug candidate for treating imatinib-resistant CML patients.

Keywords

CML; Drug resistance; Imatinib; S116836; TKI.

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