Drug Discovery 2022: driving the next life science revolution

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


C Parsy1; N Dodic1; N Ancelin1; M Bordessoules1; A Bouillot1; C Charrier1; A Laroze1; AP luzy1; A Moquette1; J pilot1; G serrin1
1 Oncodesign, France


Small molecule macrocyclic kinase inhibitors have attracted significant attention in drug discovery over the past years with drugs approval such as Lorlatinib demonstrating the clinical relevance of this approach. We developed our expertise to further optimize those cyclic molecules. Having low molecular weight, they favorably alter the biological and physiochemical properties as well as selectivity, as compared to their linear parent, yielding high-quality drug candidates. While focused on kinase inhibitors, macrocyclic derivatives could be potentially turned into bifunctional protein degraders molecules useful for selective cellular knockdown of targeted proteins and investigation of the pharmacological effects.

Our findings support the rapid derivatization of macrocyclic “probes” inhibitors into macrocyclic-PROTAC as a strategy to generate early chemical biology tools with maintained potency and selectivity between homologous targets. Optimization of the physico-chemical and ADME properties of molecules can lead to drug candidates with distinct pharmacological effects as compared to the parent linear kinase inhibitors.

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