Targeting Cullin-RING E3 Ubiquitin Ligase 4 by Small Molecule Modulators

  • J Cell Signal. 2021;2(3):195-205. doi: 10.33696/Signaling.2.051.
Kenneth Wu  1 ,  Benjamin D Hopkins  1  2 ,  Roberto Sanchez  3  4 ,  Robert J DeVita  3  4 ,  Zhen-Qiang Pan  1
Affiliations
  • 1. Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA.
  • 2. Genetics and Genomics, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA.
  • 3. Department of Pharmacological Sciences, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA.
  • 4. Drug Discovery Institute, The Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA.
PMID: 34604860 DOI: 10.33696/Signaling.2.051
Abstract

Cullin-RING E3 ubiquitin Ligase 4 (CRL4) plays an essential role in cell cycle progression. Recent efforts using high throughput screening and follow up hit-to-lead studies have led to identification of small molecules 33-11 and KH-4-43 that inhibit E3 CRL4's core Ligase complex and exhibit Anticancer potential. This review provides: 1) an updated perspective of E3 CRL4, including structural organization, major substrate targets and role in cancer; 2) a discussion of the challenges and strategies for finding the CRL inhibitor; and 3) a summary of the properties of the identified CRL4 inhibitors as well as a perspective on their potential utility to probe CRL4 biology and act as therapeutic agents.

Keywords
Cdt1; Cell cycle; E3 CRL4; Small molecule inhibitors; Tumor inhibition.
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