Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma

Journal of Medicinal Chemistry
Joshua D HansenAntonia Lopez-Girona

Abstract

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

References

Mar 13, 2010·Science·Takumi ItoHiroshi Handa
Aug 12, 2014·Nature Structural & Molecular Biology·Philip P ChamberlainBrian E Cathers
Jun 9, 2015·Chemistry & Biology·Jing LuCraig M Crews
Aug 19, 2015·Nature Chemical Biology·Raymond J Deshaies
Oct 30, 2015·Current Opinion in Cell Biology·Andrew A Guirguis, Benjamin L Ebert
Jun 25, 2016·Nature·Mary E MatyskielaPhilip P Chamberlain
Jan 24, 2018·Scientific Reports·Tomoyuki MoriToshio Hakoshima

❮ Previous
Next ❯

Citations

May 18, 2020·Pharmaceuticals·Tomoko Asatsuma-OkumuraHiroshi Handa
Jul 25, 2020·Haematologica·Annamaria Gulla, Kenneth C Anderson
Jan 13, 2021·Cell Death and Differentiation·Peter E CockramDomagoj Vucic
Feb 16, 2021·Frontiers in Oncology·Leona YamamotoKenneth Carl Anderson
Mar 7, 2021·International Journal of Molecular Sciences·Jinsha LiuSepideh Afshar
Oct 16, 2020·Haematologica·Annamaria Gulla, Kenneth C Anderson
Mar 18, 2021·Journal of Experimental Pharmacology·Massimo OffidaniAttilio Olivieri
Mar 19, 2021·Expert Review of Hematology·Michel DelforgeNicolas Kint
Mar 23, 2021·Frontiers in Immunology·Criselle D'SouzaPaul J Neeson
Sep 2, 2020·Biochimica Et Biophysica Acta. Proteins and Proteomics·Shelton R BoydDamian W Young
May 20, 2021·American Society of Clinical Oncology Educational Book·Jessica CaroFaith E Davies
Jun 7, 2021·Biomarker Research·Shichao WangShaobing Gao
Jul 29, 2021·Journal of Medicinal Chemistry·Guoqiang DongChunquan Sheng
Sep 24, 2021·Pflügers Archiv : European journal of physiology·Hyoung Kyu KimJin Han
Oct 28, 2021·Expert Opinion on Therapeutic Patents·Alexander Kazantsev, Mikhail Krasavin

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.