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

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...

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Autores principales:	Matteo Costacurta, Jackson He, Philip E. Thompson, Jake Shortt
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	thalidomide IMiDs CELMoDs Cereblon multiple myeloma Medicine R
Acceso en línea:	https://doaj.org/article/5ef44279fcee488eac1afb4b98989af1
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spelling	oai:doaj.org-article:5ef44279fcee488eac1afb4b98989af12021-11-25T18:07:51ZMolecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy10.3390/jpm111111852075-4426https://doaj.org/article/5ef44279fcee488eac1afb4b98989af12021-11-01T00:00:00Zhttps://www.mdpi.com/2075-4426/11/11/1185https://doaj.org/toc/2075-4426Thalidomide 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<sup>CRBN</sup> 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.Matteo CostacurtaJackson HePhilip E. ThompsonJake ShorttMDPI AGarticlethalidomideIMiDsCELMoDsCereblonmultiple myelomaMedicineRENJournal of Personalized Medicine, Vol 11, Iss 1185, p 1185 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	thalidomide IMiDs CELMoDs Cereblon multiple myeloma Medicine R
spellingShingle	thalidomide IMiDs CELMoDs Cereblon multiple myeloma Medicine R Matteo Costacurta Jackson He Philip E. Thompson Jake Shortt Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
description	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<sup>CRBN</sup> 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.
format	article
author	Matteo Costacurta Jackson He Philip E. Thompson Jake Shortt
author_facet	Matteo Costacurta Jackson He Philip E. Thompson Jake Shortt
author_sort	Matteo Costacurta
title	Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
title_short	Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
title_full	Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
title_fullStr	Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
title_full_unstemmed	Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
title_sort	molecular mechanisms of cereblon-interacting small molecules in multiple myeloma therapy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5ef44279fcee488eac1afb4b98989af1
work_keys_str_mv	AT matteocostacurta molecularmechanismsofcerebloninteractingsmallmoleculesinmultiplemyelomatherapy AT jacksonhe molecularmechanismsofcerebloninteractingsmallmoleculesinmultiplemyelomatherapy AT philipethompson molecularmechanismsofcerebloninteractingsmallmoleculesinmultiplemyelomatherapy AT jakeshortt molecularmechanismsofcerebloninteractingsmallmoleculesinmultiplemyelomatherapy
_version_	1718411561313239040

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

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