Thomas, Jason, Harrington, Edmund, Murphy, Jason, Jain, Rishi, Schirle, Markus, Gower, Carrie, Chang, Matthew and Maly, Dustin (2016) GENERATION OF BIVALENT KINASE INHIBITORS STARTING FROM A SINGLE POLYPHARMACOLOGICAL COMPONENT FOR SELECTIVE TARGET MODULATION IN VIVO. ACS Chemical Biology.

Abstract

While the identification of small molecule modulators of protein function remains a fundamental challenge, more challenging still is the optimization required to develop suitable tool compounds to dissect biological systems in complex settings. Bivalent inhibition is a proven in vitro strategy for simultaneously increasing potency and enhancing selectivity, however the generality of this approach can be limiting. Here we describe a modular method of generating bivalent inhibitors of protein kinases. These bivalent inhibitors are based on an engineered form of the self-labeling protein O(6)-alkylguanine-DNA alkyltransferase (SNAPtag) and are fused to an intracellular antibody capable of binding with high affinity and selectivity to their respective kinase target. The self-labeling property of SNAPtag is exploited to covalently tether a pan ATP-competitive inhibitor capable of target hundreds of protein kinases. As a demonstration of the modular nature of this approach, selective bivalent inhibitors for either Bcr-Abl or activated ERK2 were achieved starting from a single polypharmacological component. Finally, we demonstrate that a bivalent inhibitor for Abl readily assembles in cells, leading to inhibition of protein function, and emphasizing that this approach is capable of delivering tools compounds suitable for use in cellular systems.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/24153