Multi-Omics Profiling Establishes the Polypharmacology of FDA Approved CSK4/6 Inhibitors and Its Impact on Drug Response
61 Pages Posted: 17 Nov 2018 Sneak Peek Status: PublishedMore...
The target profiles of many drugs are established early in their development and are not systematically revisited at the time of approval, raising the question whether human therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five distinct phenotypic and biochemical assays to compare approved inhibitors of the cyclindependent kinases CDK4/6 (palbociclib, ribociclib, and abemaciclib) that are promising therapies for hormone-receptor positive breast cancer. We find that transcriptional, proteomic and phenotypic changes induced by the three drugs differ significantly and that abemaciclib has activates overlapping those of the older generation CDK inhibitor alvocidib. Abemaciclib’s activities arise from inhibition of kinases other than CDK4/6 including CDK2/Cyclin A/E and CDK1/Cyclin B. Our data suggest the potential for differential use in the clinic and argue that a multi-faceted experimental and computational approach is necessary to obtain a reliable picture of kinase inhibitor target spectrum.
Keywords: Therapeutics, targeted therapy; HR breast cancer; CDK4/6 inhibitors; drug profiling; drug mechanisms of action
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