Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling. Issue 1 (16th January 2020)

• Record Type: Journal Article
• Authors: You, Inchul; Erickson, Emily C.; Donovan, Katherine A.; Eleuteri, Nicholas A.; Fischer, Eric S.; Gray, Nathanael S.; Toker, Alex
• Is Part Of: Cell chemical biology. Volume 27:Issue 1(2020)
• Page Start: 66
• Page End: 73.e7
• Publication Date: 2020-01-16
• Subjects: PROTAC -- degrader -- AKT -- protein kinase -- oncogene -- PI 3-kinase; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.11.014
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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 h, even after compound washout. Our findings suggest that AKT degradation may confer prolonged pharmacological effects compared with inhibition, and highlight the potential advantages of AKT-targeted degradation. Graphical Abstract: Highlights: An AKT-selective heterobifunctional degrader was developed AKT degradation induced stronger anti-proliferative effects than AKT inhibition AKT loss and inhibition of downstream signaling was sustained, even after washout Abstract : You and Erickson et al. report the development and characterization of INY-03-041, a highly selective AKT degrader. The authors demonstrate that INY-03-041 not only exhibits more potent anti-proliferative effects than the catalytic inhibitor GDC-0068, but also induces sustained AKT destabilization and inhibition of downstream signaling, even after compound washout.