PT - JOURNAL ARTICLE AU - Palani Kirubakaran AU - George Morton AU - Pingfeng Zhang AU - Hanghang Zhang AU - John Gordon AU - Magid Abou-Gharbia AU - Jean-Pierre J. Issa AU - Jinhua Wu AU - Wayne Childers AU - John Karanicolas TI - Comparative Modeling of CDK9 Inhibitors to Explore Selectivity and Structure-Activity Relationships AID - 10.1101/2020.06.08.138602 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.06.08.138602 4099 - http://biorxiv.org/content/early/2020/06/09/2020.06.08.138602.short 4100 - http://biorxiv.org/content/early/2020/06/09/2020.06.08.138602.full AB - Cyclin-dependent kinase 9 (CDK9) plays a key role in transcription elongation, and more recently it was also identified as the molecular target of a series of diaminothiazole compounds that reverse epigenetic silencing in a phenotypic assay. To better understand the structural basis underlying these compounds’ activity and selectivity, we developed a comparative modeling approach that we describe herein. Briefly, this approach draws upon the strong structural conservation across the active conformation of all protein kinases, and their shared pattern of interactions with Type I inhibitors. Because of this, we hypothesized that the large collection of inhibitor/kinase structures available in the Protein Data Bank (PDB) would enable accurate modeling of this diaminothiazole series in complex with each CDK family member. We apply this new comparative modeling pipeline to build each of these structural models, and then demonstrate that these models provide retrospective rationale for the structure-activity relationships that ultimately guided optimization to the lead diaminothiazole compound MC180295 (14e). We then solved the crystal structure of the 14e/CDK9 complex, and found the resulting structure to be in excellent agreement with our corresponding comparative model. Finally, inspired by these models, we demonstrate how structural changes to 14e can be used to rationally tune this compound’s selectivity profile. With the emergence of CDK9 as a promising target for therapeutic intervention in cancer, we anticipate that comparative modeling can provide a valuable tool to guide optimization of potency and selectivity of new inhibitors targeting this kinase.Competing Interest StatementMC180295 and related compounds are covered under a patent held by Temple University, with some of these co-authors listed as inventors and entitled to a share of licensing rights and/or royalties. J-P.J.I. is co-founder of EpiGenOnco, which holds an option to license MC180295 and related compounds.