TY - JOUR

T1 - The role of E3 ubiquitin ligase in multiple myeloma

T2 - potential for cereblon E3 ligase modulators in the treatment of relapsed/refractory disease

AU - Richardson, Paul G.

AU - Mateos, María Victoria

AU - Vangsted, Annette J.

AU - Ramasamy, Karthik

AU - Abildgaard, Niels

AU - Ho, P. Joy

AU - Quach, Hang

AU - Bahlis, Nizar J.

N1 - Publisher Copyright: © 2022 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2022

Y1 - 2022

N2 - Introduction: Insights into the mechanisms of protein homeostasis and proteasomal degradation have led to new strategies of redirecting the ubiquitin–proteasome system (UPS) to reduce or eliminate proteins or survival factors key to malignant pathobiology, multiple myeloma (MM) in particular. These strategies have enabled researchers to target proteins that were previously considered difficult to modulate by pharmacological means. Areas covered: This review provides a brief overview of UPS biology, particularly the role of the CRL4CRBN E3 ubiquitin ligase complex, and summarizes current strategies for co-opting the UPS, including CELMoD compounds, SNIPERs, PROTACs, and degronimids. A detailed discussion is provided on lead CELMoD compounds iberdomide and mezigdomide, which are currently being evaluated in clinical trials in patients with MM. Expert opinion: Since a high proportion of patients develop drug resistance, it is vital to have novel therapeutic agents for treating relapsed patients with MM more effectively. It is encouraging that the expanding pathophysiological insight into cellular signaling pathways in MM increasingly translates into the development of novel therapeutic agents such as targeted protein degraders. This holds promise for improving outcomes in MM and beyond.

AB - Introduction: Insights into the mechanisms of protein homeostasis and proteasomal degradation have led to new strategies of redirecting the ubiquitin–proteasome system (UPS) to reduce or eliminate proteins or survival factors key to malignant pathobiology, multiple myeloma (MM) in particular. These strategies have enabled researchers to target proteins that were previously considered difficult to modulate by pharmacological means. Areas covered: This review provides a brief overview of UPS biology, particularly the role of the CRL4CRBN E3 ubiquitin ligase complex, and summarizes current strategies for co-opting the UPS, including CELMoD compounds, SNIPERs, PROTACs, and degronimids. A detailed discussion is provided on lead CELMoD compounds iberdomide and mezigdomide, which are currently being evaluated in clinical trials in patients with MM. Expert opinion: Since a high proportion of patients develop drug resistance, it is vital to have novel therapeutic agents for treating relapsed patients with MM more effectively. It is encouraging that the expanding pathophysiological insight into cellular signaling pathways in MM increasingly translates into the development of novel therapeutic agents such as targeted protein degraders. This holds promise for improving outcomes in MM and beyond.

KW - CELMoD compounds

KW - cereblon

KW - degronimids

KW - E3 ubiquitin ligase

KW - iberdomide

KW - IMiD agents

KW - mezigdomide

KW - multiple myeloma

KW - PROTACs

KW - SNIPERs

U2 - 10.1080/14789450.2022.2142564

DO - 10.1080/14789450.2022.2142564

M3 - Review

C2 - 36342226

AN - SCOPUS:85141720365

VL - 19

SP - 235

EP - 246

JO - Expert Review of Proteomics

JF - Expert Review of Proteomics

SN - 1478-9450

IS - 4-6

ER -