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

Authors
  • Gupta, Pranav1
  • Zhang, Guan-Nan1
  • Barbuti, Anna Maria1
  • Zhang, Xin2
  • Karadkhelkar, Nishant1
  • Zhou, Jingfeng3
  • Ding, Ke2
  • Pan, Jingxuan3
  • Yoganathan, Sabesan1
  • Yang, Dong-Hua4
  • Chen, Zhe-Sheng5
  • 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. , (China)
  • 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. , (China)
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA. Electronic address: [email protected]
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cancer letters
Publication Date
Mar 01, 2020
Volume
472
Pages
132–141
Identifiers
DOI: 10.1016/j.canlet.2019.11.040
PMID: 31837444
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2019 Elsevier B.V. All rights reserved.

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