Unconventional Strategies to Target Challenging Enzymes Using Small-Molecule Covalent Inhibitors

Abstract

Unconventional strategies employing covalent small molecules were investigated to down-regulate signaling pathways mediated by enzymes that are challenging to target. First, Her3 was selectively degraded using covalent small molecules, which resulted in down-regulation of Her3 signaling pathways (Chapter 1). Her3 is considered as a `pseudokinase' as it has very low kinase activity. Potent covalent Her3 binders such as SML-4-82-1 were developed by structure-based drug design, but these compounds were ineffective in inhibiting Her3 signaling. Presumably, Her3 can still activate its signaling through formation of an asymmetric dimer even in the presence of potent Her3 binders. Instead, selective Her3 degradation was pursued by taking advantage of the Ubiquitin-Proteasome system. In situ ligation of the covalent Her3 binders to E3 ligase recognizing elements inside Her3-dependent cell lines degraded Her3, and inhibited activation of Her3 and its down-stream kinases.