PMID- 34855399 OWN - NLM STAT- MEDLINE DCOM- 20220121 LR - 20221224 IS - 1520-4804 (Electronic) IS - 0022-2623 (Print) IS - 0022-2623 (Linking) VI - 64 IP - 24 DP - 2021 Dec 23 TI - Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders. PG - 18054-18081 LID - 10.1021/acs.jmedchem.1c01476 [doi] AB - The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure-activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders: von Hippel-Lindau (VHL)-recruiting degrader 13 (MS98) and cereblon (CRBN)-recruiting degrader 25 (MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders 13 and 25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo. FAU - Yu, Xufen AU - Yu X AD - Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. FAU - Xu, Jia AU - Xu J AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. FAU - Xie, Ling AU - Xie L AD - Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States. FAU - Wang, Li AU - Wang L AD - Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States. FAU - Shen, Yudao AU - Shen Y AD - Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. FAU - Cahuzac, Kaitlyn M AU - Cahuzac KM AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. FAU - Chen, Xian AU - Chen X AD - Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States. FAU - Liu, Jing AU - Liu J AD - Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. FAU - Parsons, Ramon E AU - Parsons RE AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. FAU - Jin, Jian AU - Jin J AUID- ORCID: 0000-0002-2387-3862 AD - Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. AD - Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States. LA - eng GR - S10 OD028504/OD/NIH HHS/United States GR - R35 CA220491/CA/NCI NIH HHS/United States GR - T32 CA078207/CA/NCI NIH HHS/United States GR - S10 OD025132/OD/NIH HHS/United States GR - P30 CA196521/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20211202 PL - United States TA - J Med Chem JT - Journal of medicinal chemistry JID - 9716531 RN - 0 (Piperazines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 524Y3IB4HQ (ipatasertib) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Biological Availability MH - Cell Line, Tumor MH - *Drug Design MH - Humans MH - Mice MH - Piperazines/chemical synthesis/*chemistry/*pharmacology MH - Protein Kinase Inhibitors/chemical synthesis/*chemistry/*pharmacology MH - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors MH - Pyrimidines/chemical synthesis/*chemistry/*pharmacology MH - Structure-Activity Relationship PMC - PMC8819633 MID - NIHMS1770401 COIS- The authors declare the following competing financial interest(s): J.J., R.P., J.L. J.X. and X.Y. are inventors of a patent application filed by the Icahn School of Medicine at Mount Sinai. J.J. is a cofounder, scientific advisory board member and equity shareholder in Cullgen Inc. and a consultant for Cullgen Inc., EpiCypher Inc., and Accent Therapeutics Inc. R.P. is a shareholder and advisor of Therapten Bioscience, Inc. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, and Cullgen, Inc. EDAT- 2021/12/03 06:00 MHDA- 2022/01/22 06:00 PMCR- 2022/12/23 CRDT- 2021/12/02 17:17 PHST- 2021/12/03 06:00 [pubmed] PHST- 2022/01/22 06:00 [medline] PHST- 2021/12/02 17:17 [entrez] PHST- 2022/12/23 00:00 [pmc-release] AID - 10.1021/acs.jmedchem.1c01476 [doi] PST - ppublish SO - J Med Chem. 2021 Dec 23;64(24):18054-18081. doi: 10.1021/acs.jmedchem.1c01476. Epub 2021 Dec 2.