Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader.

AKT and associated signaling pathways have been recognized as promising therapeutic targets for decades, and growing evidence indicates that inhibition or degradation of cellular AKT are viable strategies to treat cancer. Guided by an in silico modeling approach for rational linker design and based on our previous work in this field, we herein efficiently synthesized a small group of cereblon-recruiting AKT PROTAC molecules and identified a highly potent AKT degrader B4. Compared to the existing AKT degraders, B4 has a structurally unique AKT targeting warhead derived from the pyrazole-furan conjugated piperidine derivatives. It induces selective degradation of all three isoforms of AKT and exhibits efficacious anti-proliferation against several human hematological cancers. Notably, B4 demonstrates potent inhibition of AKT downstream signaling superior to its parental inhibitor. Together with its active analogs, B4 expands the arsenal of AKT chemical degraders as a valuable probe to uncover AKTs new functions and as a potential drug candidate to treat cancer. [Display omitted] • Structure-based rational linker design enables efficient discovery of AKT degrader B4. • B4 rapidly depletes cellular AKT and strongly suppresses AKT downstream signaling. • B4 potently inhibits MCL and MM cell growth and synergizes with Ibrutinib in cells. [ABSTRACT FROM AUTHOR]