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 CRL4CRBN 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.
Highlights
Thalidomide analogues, such as lenalidomide and pomalidomide, have significantly improved outcomes for patients with multiple myeloma (MM), an incurable malignancy of the plasma cell [1,2]
Before CRBN was identified as the protein target of imide drugs (IMiDs), a CRBN germline nonsense mutation was implicated in an autosomal recessive form of mental retardation [3,4]
The potency and acute kinetics of IKZF3 degradation are greater with iberdomide relative to pomalidomide, which may explain its activity in IMiD-refractory patients [49]
Summary
Thalidomide analogues, such as lenalidomide and pomalidomide, have significantly improved outcomes for patients with multiple myeloma (MM), an incurable malignancy of the plasma cell [1,2]. Lenalidomide impairs angiogenesis by a reduction in VEGF expression, together with inhibition of fibroblast growth factor (FGF) and interleukin (IL)-6 signaling, and shows increased anti-angiogenic activity relative to thalidomide [32,33,34]. Recent deep sequencing work has demonstrated that point mutations, copy number loss and structural variants of CRBN can impair responses to lenalidomide and pomalidomide, and that these aberrations significantly reduce the survival of MM patients [45]. Together these data indicate that CRBN downregulation and/or mutations appear to represent the main mechanism by which MM cells escape the anti-cancer effects of IMiDs in vivo
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