Small Molecule Modulators of RING-Type E3 Ligases: MDM and Cullin Families as Targets

Abstract

Ubiquitin-proteasome system (UPS) is a primary signaling pathway for regulation of intracellular protein levels. E3 ubiquitin ligases, substrate-specific members of the UPS, represent highly attractive protein targets for drug discovery. The importance of E3 ligases as prospective targets for small molecule modulation is reinforced by ever growing evidence of their role in cancer and other diseases. To date the number of potent compounds targeting E3 ligases remains rather low and their rational design constitutes a challenging task. To successfully address this problem one must take into consideration the multi-subunit nature of many E3 ligases that implies multiple druggable pockets and protein-protein interfaces. In this review, we briefly cover the current state of drug discovery in the field of RING-type E3 ligases with focus on MDM and Cullin families as targets. We also provide an overview of small molecule chimeras that induce RING-type E3-mediated proteasomal degradation of substrate proteins of interest.

Keywords: Cullin family; MDM family; PROTACs; RING-type E3 ligases; SNIPERs; induced protein degradation; small molecules; ubiquitin–proteasome system.

FIGURE 1

Structural organization of (A) MDM and (B) CRL RING-type E3 ubiquitin ligases and a brief list of their most potent modulators. MDM2 and MDM4 are single subunit proteins containing C-terminal RING finger domain. In contrast, CRLs are constituted of several subunits, such as receptor, adaptor, Cullin scaffold and RING-box protein. (C) Schematic representation of PROTAC/SNIPER molecule acting to induce ubiquitination and subsequent proteasomal degradation of substrate protein of interest. These small molecule degraders contain substrate-specific component, short linker, and E3-specific component.