Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.

Basic Information

ID: ALA4627338

Journal: Bioorg Med Chem Lett

Title: Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.

Authors: Anderson NA, Cryan J, Ahmed A, Dai H, McGonagle GA, Rozier C, Benowitz AB.

Abstract: Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.

CiteXplore: 32184044

DOI: 10.1016/j.bmcl.2020.127106

Patent ID: ┄