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Cell Chem Biol. 2020 Jan 16;27(1):66-73.e7. doi: 10.1016/j.chembiol.2019.11.014. Epub 2019 Dec 16.

Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
2
Department of Pathology, Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: nathanael_gray@dfci.harvard.edu.
5
Department of Pathology, Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: atoker@bidmc.harvard.edu.

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 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.

KEYWORDS:

AKT; PI 3-kinase; PROTAC; degrader; oncogene; protein kinase

PMID:
31859249
PMCID:
PMC6980747
[Available on 2021-01-16]
DOI:
10.1016/j.chembiol.2019.11.014

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