Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells.
Xu F, Zhang X, Chen Z, He S, Guo J, Yu L, Wang Y, Hou C, Ai-Furas H, Zheng Z, Smaill JB, Patterson AV, Zhang ZM, Chen L, Ren X, Ding K.
EGFR inhibitor therapies have brought significant benefit to NSCLC patients. However, all patients gradually progress to acquired resistance <i>via</i> diverse mechanisms. Akt3 overexpression but not Akt1/2 is one of the found molecular events that mediate osimertinib (<b>1</b>) resistance in NSCLC patients. Here, we report <b>12l</b> as the first bona fide isoform-selective Akt3 degrader which potently induced proteasomal degradation of the target both <i>in vitro</i> and <i>in vivo</i>, whereas its effects on Akt1/2 were minimal. Using <b>12l</b> as a tool, non-canonical function of Akt3 was validated to contribute greatly to survival of <b>1</b>-resistant H1975OR NSCLC cells. Degrader <b>12l</b> potently suppressed the growth of H1975OR as well as several NSCLC cell lines with low nanomolar IC<sub>50</sub> values and demonstrated promising <i>in vivo</i> 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.