Proteolysis Targeting Chimera (PROTAC) Linkerology Enhances the CDK-Degradation Selectivity Profile of a Multi-CDK Inhibitor: Discovery of Potent, Anti-Leukemic CDK9 Degraders. (PubMed, ACS Pharmacol Transl Sci) - Oct 4, 2026 - "Based on the prior serendipitous discovery of the cyclin-dependent kinase 9 (CDK9)-selective PROTAC degrader "THAL-SNS-032", developed from the multi-CDK2/CDK7/CDK9 inhibitor SNS-032, we speculated that other multi-CDK inhibitors might likewise be transformed into CDK9-selective PROTACs, establishing a "linkerology" platform approach to enhancing CDK family member specificity (and beyond)...Accordingly, we built candidate PROTACs by linking AT7519 to one of two thalidomide derivatives; those molecules in which AT7519 and the thalidomide derivative were coupled via rigid linkers caused greater degradation of the CDK9 protein than those with more flexible linkers...In summary, we demonstrate that converting a multi-CDK inhibitor into a PROTAC with selectivity for CDK9 over other family members is not an isolated phenomenon. Our findings further support the concept that PROTAC linkerology may serve as a platform for enhancing kinase..."
Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CDK1 • CDK4 • CDK6 • CDK7 • CDK9 • CRBN • MYCN
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Alexander D MacKerell; Alexandria M Chan; Brandon A Carter-Cooper; Christian Eberly; Christopher C Goodis; Curt I Civin; Erik B Nordquist; Maureen A Kane; Mehari Weldemariam; Rena Lapidus; Sarah Pogash; Steven Fletcher
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