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

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

  • Eur J Med Chem. 2023 Jun 5;254:115342. doi: 10.1016/j.ejmech.2023.115342.
Robert J Tokarski 2nd 1,  Chia M Sharpe 2,  Andrew C Huntsman 1,  Brittney K Mize 1,  Oluwatosin R Ayinde 1,  Emily H Stahl 3,  James R Lerma 2,  Andrew Reed 4,  Bridget Carmichael 3,  Natarajan Muthusamy 3,  John C Byrd 5,  James R Fuchs 6
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, United States.
  • 2 Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, United States.
  • 3 The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, 43210, United States.
  • 4 CCIC Mass Spectrometry and Proteomics, The Ohio State University, Columbus, OH, 43210, United States.
  • 5 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.
  • 6 Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, United States. Electronic address: fuchs.42@osu.edu.
PMID: 37071962 DOI: 10.1016/j.ejmech.2023.115342
Abstract

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.

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