2. Academic Validation
  3. Reinvent Aliphatic Arsenicals as Reversible Covalent Warheads toward Targeted Kinase Inhibition and Non-acute Promyelocytic Leukemia Cancer Treatment

Reinvent Aliphatic Arsenicals as Reversible Covalent Warheads toward Targeted Kinase Inhibition and Non-acute Promyelocytic Leukemia Cancer Treatment

  • J Med Chem. 2024 Apr 11;67(7):5458-5472. doi: 10.1021/acs.jmedchem.3c02076.
Yang Zhao 1,  Xinyue Zhao 1,  Lewei Duan 2,  Ruxue Hou 1,  Yuxin Gu 1,  Zhen Liu 1,  Jianbin Chen 1,  Feizhen Wu 2 3,  Limin Yang 1,  X Chris Le 4,  Qiuquan Wang 1,  Xiaowen Yan 1 5
Affiliations

Affiliations

  • 1 Department of Chemistry and the MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
  • 2 Laboratory of Epigenetics at Institutes of Biomedical Sciences and Intelligent Medicine Institute, Fudan University, Shanghai 200032, China.
  • 3 Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
  • 4 Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2G3, Canada.
  • 5 Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen 361005, China.
PMID: 38556750 DOI: 10.1021/acs.jmedchem.3c02076
Abstract

The success of arsenic in acute promyelocytic leukemia (APL) treatment is hardly transferred to non-APL cancers, mainly due to the low selectivity and weak binding affinity of traditional arsenicals to oncoproteins critical for Cancer survival. We present herein the reinvention of aliphatic trivalent arsenicals (As) as reversible covalent warheads of As-based targeting inhibitors toward Bruton's tyrosine kinase (Btk). The effects of As warheads' valency, thiol protection, methylation, spacer length, and size on inhibitors' activity were studied. We found that, in contrast to the bulky and rigid aromatic As warhead, the flexible aliphatic As warheads were well compatible with the well-optimized guiding group to achieve nanomolar inhibition against Btk. The optimized As inhibitors effectively blocked the BTK-mediated oncogenic signaling pathway, leading to elevated antiproliferative activities toward lymphoma cells and xenograft tumor. Our study provides a promising strategy enabling rational design of new aliphatic arsenic-based reversible covalent inhibitors toward non-APL Cancer treatment.

Figures
Products