Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy

Matteo Costacurta; Jackson He; Philip E Thompson; Jake Shortt

doi:10.3390/jpm11111185

Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy

J Pers Med. 2021 Nov 11;11(11):1185. doi: 10.3390/jpm11111185.

Authors

Matteo Costacurta^{1

2}, Jackson He^{1

2

3}, Philip E Thompson³, Jake Shortt^{1

2}

Affiliations

¹ Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
² Monash Haematology, Monash Health, Clayton, VIC 3168, Australia.
³ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.

Abstract

Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of 'neosubstrates', Ikaros (IKZF1) and Aiolos (IKZF3), conveying concurrent antimyeloma activity and T-cell costimulation. There is now a greater understanding of physiological CRBN functions, including endogenous substrates and chaperone activity. CRISPR Cas9-based genome-wide screening has further elucidated the complex cellular machinery implicated in IMiD sensitivity, including IKZF1/3-independent mechanisms. New-generation IMiD derivatives with more potent anti-cancer properties-the CELMoDs (Cereblon E3 ligase modulators)-are now being evaluated. Rational drug design also allows 'hijacking' of CRL4^CRBN utilising proteolysis targeting chimeras (PROTACs) to convey entirely distinct substrate repertoires. As all these chemotypes-thalidomide, IMiDs, CELMoDs and PROTACs-engage CRBN and modify its functions, we describe them here in aggregate as 'CRBN-interacting small molecules' (CISMs). In this review, we provide a contemporary summary of the biological consequences of CRBN modulation by CISMs. Detailed molecular insight into CRBN-CISM interactions now provides an opportunity to more effectively target previously elusive cancer dependencies, representing a new and powerful tool for the implementation of precision medicine.

Keywords: CELMoDs; Cereblon; IMiDs; multiple myeloma; thalidomide.

Publication types

Review

Abstract

Publication types

Grants and funding