Bifunctional degraders of cyclin dependent kinase 9 (CDK9): Probing the relationship between linker length, properties, and selective protein degradation.

Autor: Tokarski RJ 2nd; Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, United States., Sharpe CM; Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, United States., Huntsman AC; Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, United States., Mize BK; Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, United States., Ayinde OR; Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, United States., Stahl EH; The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, 43210, United States., Lerma JR; Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, United States., Reed A; CCIC Mass Spectrometry and Proteomics, The Ohio State University, Columbus, OH, 43210, United States., Carmichael B; The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, 43210, United States., Muthusamy N; The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, 43210, United States., Byrd JC; Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, United States; University of Cincinnati Cancer Center, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, United States., Fuchs JR; Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, United States. Electronic address: fuchs.42@osu.edu.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Jun 05; Vol. 254, pp. 115342. Date of Electronic Publication: 2023 Apr 05.
DOI: 10.1016/j.ejmech.2023.115342
Abstrakt: Cyclin-dependent kinase 9 (CDK9) is a promising therapeutic target in multiple cancer types, including acute myeloid leukemia (AML). Protein degraders, also known as proteolysis targeting chimeras (PROTACs), have emerged as tools for the selective degradation of cancer targets, including CDK9, complementing the activity of traditional small-molecule inhibitors. These compounds typically incorporate previously reported inhibitors and a known E3 ligase ligand to induce ubiquitination and subsequent degradation of the target protein. Although many protein degraders have been reported in the literature, the properties of the linker necessary for efficient degradation still require special attention. In this study, a series of protein degraders was developed, employing the clinically tested CDK inhibitor AT7519. The purpose of this study was to examine the effect that linker composition, specifically chain length, would have on potency. In addition to establishing a baseline of activity for various linker compositions, two distinct homologous series, a fully alkyl series and an amide-containing series, were prepared, demonstrating the dependence of degrader potency in these series on linker length and the correlation with predicted physicochemical properties.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrew C. Huntsman reports financial support was provided by American Chemical Society MEDI Division. Robert J. Tokarski reports financial support was provided by American Foundation for Pharmaceutical Education. Oluwatosin R. Ayinde reports financial support was provided by American Society of Hematology. James R. Fuchs has patent #DESIGN AND OPTIMIZATION OF CDK9 DEGRADERS FOR IN VIVO ACTIVITY TO EFFECTIVELY TARGET ACUTE MYELOID LEUKEMIA pending to The Ohio State University.
(Copyright © 2023. Published by Elsevier Masson SAS.)
Databáze: MEDLINE
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