Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling

Abstract

The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Our findings indicate that AKT degradation may confer prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.

Down-regulation of AKT proteins slows the growth of mutant-KRAS pancreatic tumors

“…Recently, there has been the development of a new strategy for targeting kinases including AKT by co-opting proteasome-mediated degradation [10]. The AKT degraders were designed based on AKT inhibitors, but they possess additional chemical groups so that they can engage ubiquitin ligases leading to the degradation of target proteins through proteasomes [11][12][13][49][50][51][52]. A number of studies have found that this novel class of compounds is more effective than their parental AKT inhibitors in suppressing downstream signaling and reducing cancer cell growth.…”

“…In recent publications, You, et al developed new compounds that can recruit ubiquitin ligase E3 to downregulate AKT proteins through proteasome degradation [12,13]. We first compared the AKT degrader (INY-05-040) versus the clinically tested AKT catalytic inhibitor (GDC0068 or ipatasertib) in the human pancreatic cancer cell line PANC-1, low-passage patient-derived pancreatic cancer cells UM5, and a pancreatic cancer cell line derived from the KPC mouse model (Kras G12D ; Trp53 R172H ; Pdx1-Cre).…”