机构：[1]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, Guangzhou 510632, China.[2]The First Affiliated Hospital (Huaqiao Hospital), Jinan University, Guangzhou 510632, China.[3]MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.[4]Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1142, New Zealand.[5]State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 210530, China.
EGFR inhibitor therapies have brought significant benefit to NSCLC patients. However, all patients gradually progress to acquired resistance via diverse mechanisms. Akt3 overexpression but not Akt1/2 is one of the found molecular events that mediate osimertinib (1) resistance in NSCLC patients. Here, we report 12l as the first bona fide isoform-selective Akt3 degrader which potently induced proteasomal degradation of the target both in vitro and in vivo, whereas its effects on Akt1/2 were minimal. Using 12l as a tool, non-canonical function of Akt3 was validated to contribute greatly to survival of 1-resistant H1975OR NSCLC cells. Degrader 12l potently suppressed the growth of H1975OR as well as several NSCLC cell lines with low nanomolar IC50 values and demonstrated promising in vivo antitumor efficacy in nude mice bearing H1975OR or PC9 NSCLC xenograft models. Selective degradation of Akt3 may be considered as a novel strategy for human cancer therapy.
基金：
National
Natural Science Foundation of China (grant nos. 22037003,
81820108029, 21807044, 81874284, and 81972778), Guangdong
Province (2018B030337001, 2018A030313685, and
2022A1515011020), and Shenzhen Bay Laboratory Open
Fund (SZBL2021080601004)
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|1 区医学
小类|1 区药物化学
最新[2025]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, Guangzhou 510632, China.[2]The First Affiliated Hospital (Huaqiao Hospital), Jinan University, Guangzhou 510632, China.
共同第一作者：
通讯作者：
通讯机构：[1]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, Guangzhou 510632, China.[2]The First Affiliated Hospital (Huaqiao Hospital), Jinan University, Guangzhou 510632, China.[5]State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 210530, China.
推荐引用方式(GB/T 7714)：
Xu Fang,Zhang Xin,Chen Zhipeng,et al.Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells[J].Journal of medicinal chemistry.2022,doi:10.1021/acs.jmedchem.2c01246.
APA：
Xu Fang,Zhang Xin,Chen Zhipeng,He Sheng,Guo Jing...&Ding Ke.(2022).Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells.Journal of medicinal chemistry,,
MLA：
Xu Fang,et al."Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells".Journal of medicinal chemistry .(2022)
医学