Discovery of Potent, Selective, and In Vivo Efficacious AKT Kinase Protein Degraders via Structure-Activity Relationship Studies

Xufen Yu; Jia Xu; Yudao Shen; Kaitlyn M Cahuzac; Kwang-Su Park; Brandon Dale; Jing Liu; Ramon E Parsons; Jian Jin

doi:10.1021/acs.jmedchem.1c02165

Discovery of Potent, Selective, and In Vivo Efficacious AKT Kinase Protein Degraders via Structure-Activity Relationship Studies

J Med Chem. 2022 Feb 24;65(4):3644-3666. doi: 10.1021/acs.jmedchem.1c02165. Epub 2022 Feb 4.

Authors

Xufen Yu^{1

2}, Jia Xu², Yudao Shen^{1

2}, Kaitlyn M Cahuzac², Kwang-Su Park^{1

2}, Brandon Dale^{1

2}, Jing Liu^{1

2}, Ramon E Parsons², Jian Jin^{1

2}

Affiliations

¹ Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
² Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Abstract

We recently reported a potent, selective, and in vivo efficacious AKT degrader, MS21, which is a von Hippel-Lindau (VHL)-recruiting proteolysis targeting chimera (PROTAC) based on the AKT inhibitor AZD5363. However, no structure-activity relationship (SAR) studies that resulted in this discovery have been reported. Herein, we present our SAR studies that led to the discovery of MS21, another VHL-recruiting AKT degrader, MS143 (compound 20) with similar potency as MS21, and a novel cereblon (CRBN)-recruiting PROTAC, MS5033 (compound 35). Compounds 20 and 35 induced rapid and robust AKT degradation in a concentration- and time-dependent manner via hijacking the ubiquitin-proteasome system. Compound 20 suppressed cell growth more effectively than AZD5363 in multiple cancer cell lines. Furthermore, 20 and 35 displayed good plasma exposure levels in mice and are suitable for in vivo efficacy studies. Lastly, compound 20 effectively suppressed tumor growth in vivo in a xenograft model without apparent toxicity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Biological Availability
Cell Division / drug effects
Cell Line, Tumor
Dose-Response Relationship, Drug
Humans
Male
Mice
Mice, Nude
PC-3 Cells
Proteasome Endopeptidase Complex / drug effects
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Proteolysis
Proto-Oncogene Proteins c-akt / chemistry
Proto-Oncogene Proteins c-akt / metabolism*
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology
Pyrroles / chemical synthesis
Pyrroles / pharmacology
Structure-Activity Relationship
Tumor Stem Cell Assay
Ubiquitin / genetics
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Ubiquitin
Proto-Oncogene Proteins c-akt
Proteasome Endopeptidase Complex
capivasertib

Abstract

Publication types

MeSH terms

Substances

Grants and funding