INY-03-041, a potent and highly selective PROTAC-based pan-AKT degrader, inhibits AKT1, AKT2, and AKT3 with IC50s of 2.0 nM, 6.8 nM, and 3.5 nM, respectively. This compound consists of the ATP-competitive AKT inhibitor GDC-0068 conjugated to Lenalidomide.

Akt1:2.0 nM, Cereblon:, Akt3:3.5 nM, Akt2:6.8 nM

INY-03-041 exhibits potent in vitro inhibition of S6K1 (IC50 =37.3 nM) and PKG1 (IC50 = 33.2 nM). INY-03-041 displays enhanced anti-proliferative effects compared with GDC-0068 in MDA-MB-468 and HCC1937 cells.INY-03-041 (10-1000 nM; 2-24 hours; MDA-MB-468 cells) treatment induces potent degradation of all three AKT isoforms in a dose-dependent manner after a 12-h treatment, with maximal degradation observed between 100 and 250 nM. At concentrations of 500 nM and greater, AKT degradation is diminished. Treatment with 250 nM of INY-03-041 over time reveals partial degradation of all AKT isoforms within 4 h and progressive loss of AKT abundance out to 24 h.