Design, synthesis, and biological evaluation of Bcr-Abl PROTACs to overcome T315I mutation.

Author: Liang JIANG ¹ ; Yuting WANG ¹ ; Qian LI ¹ ; Zhengchao TU ¹ ; Sihua ZHU ¹ ; Sanfang TU ² ; Zhang ZHANG ¹ ; Ke DING ¹ ; Xiaoyun LU ¹
Author Information

1. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of China, School of Pharmacy, Jinan University, Guangzhou 510632, China.
2. Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Publication Type:Journal Article
Keywords: ALL, acute lymphoblastic leukemia; CML; CML, chronic myeloid leukemia; CRBN, cereblon; Clinical resistance; Co-IP, co-immunoprecipitation; DR, degradation rate; Degradation; IC50, cellular inhibition; LSCs, leukemic stem cells; NMPA, National Medical Products Administration; PROTAC; PROTAC, proteolysis-targeting chimeric; Ph+, Philadelphia chromosome; T315I mutation; T315I, threonine 315 to isoleucine 315; TGI, tumor growth inhibition; VHL, von Hippel-Lindau; cIAP1, cellular inhibitor of apoptosis protein 1
From: Acta Pharmaceutica Sinica B 2021;11(5):1315-1328
CountryChina
Language:English
Abstract: Bcr-Abl threonine 315 to isoleucine 315 (T315I) gatekeeper mutation induced drug resistance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia (CML). Chemical degradation of Bcr-Abl