Structure-Based Design of small macrocyclic CDK9 degraders as chemical biology tools and beyond

Authors: Nerina Dodic, Nicolas Ancellin, Anne Bouillot, Nathan Butin, Cedric Charrier, Marie-Hélène Fouchet, Alain Laroze, Anne-Pascale Luzy, Alexandre Moquette, Guillaume Serin, Christophe Parsy

Abstract: With small macrocyclic “probes” from our proprietary library in the low nanomolar range IC50, we turned our attention to CDK9 inhibitors with good selectivity profile against CDK1/2/5/7 as a starting point for building bifunctional small macrocyclic kinase degraders. Although the ATP binding site of the CDKs are structurally similar, developing a small macrocyclic PROTAC degrader could enhanced the selectivity of the parent molecule by preferential ubiquitination of lysine exposed residues among the different CDKs…

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