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Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube SWCNT-delivered MALAT1 Antisense Oligos
Published on: December 13, 2018
Saga of MCL1 inhibitors in multiple myeloma
Emily Nelson1, Sandesh P Telang2, Tulin Budak-Alpdogan3
1Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, USA.
Abstract:
Myeloid cell leukemia 1 (MCL1) is an anti-apoptotic protein within the B-cell lymphoma 2(Bcl-2) family that is aberrantly overexpressed in many cancers such as Multiple Myeloma (MM). The protein is a key contributor to MM relapses, and effectively inhibiting MCL1 is a solution to overcoming drug resistance. Since MCL1 was identified in 1993, significant progress has been made in investigating the protein's role in cancer development and the benefits of inhibition. After years of research, in 2008 AbbVie developed the first small molecule inhibitor, A-1210477, with an indole-2-carboxylic acid core that targeted MCL1's BH3 binding groove selectively and had low affinity for Bcl-2 and Bcl-xL. Following this, there was a surge in the development of novel MCL1 inhibitors, which are still being produced today. In 2016, the first MCL1 SMI, AMG 176, advanced to a phase 1 clinical trial for relapsed/refractory (R/R) MM patients and was sponsored by Amgen (NCT02675452). Spanning 8 years, this trial is the longest to date among all studies investigating MCL1 inhibition in patients with R/R MM. Six novel MCL1 inhibitors have been evaluated in clinical trials for R/R MM patients, sponsored by six different pharmaceutical companies. Adverse side effects and particularly cardiotoxicity present a significant barrier to the widespread clinical use of MCL1 inhibitors. This review explores the history and progress of MCL1 inhibition in MM through highlighting molecular methods of inhibition, early and current preclinical small molecule inhibitors, and past and present MCL1 inhibitor clinical trials for R/R MM.
Insights
Myeloid cell leukemia 1 (MCL1) protein is a key target for overcoming drug resistance in Multiple Myeloma (MM). This review details the history and progress of MCL1 inhibitors in MM clinical trials, noting challenges like cardiotoxicity.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Myeloid cell leukemia 1 (MCL1) is an anti-apoptotic protein overexpressed in cancers like Multiple Myeloma (MM), contributing to drug resistance.
- Inhibition of MCL1 is a promising strategy to overcome treatment resistance in MM.
- The development of MCL1 inhibitors has progressed significantly since its identification in 1993.
Purpose of the Study:
- To review the historical development and current progress of MCL1 inhibition strategies for Multiple Myeloma.
- To highlight molecular methods, preclinical small molecule inhibitors, and clinical trials of MCL1 inhibitors in R/R MM.
- To discuss the challenges, including adverse effects like cardiotoxicity, associated with MCL1 inhibitors.
Main Methods:
- Literature review of MCL1 inhibition in Multiple Myeloma.
- Analysis of historical and current preclinical small molecule inhibitors targeting MCL1.
- Examination of clinical trial data for MCL1 inhibitors in relapsed/refractory MM patients.
Main Results:
- The first selective MCL1 inhibitor (A-1210477) was developed in 2008.
- Six novel MCL1 inhibitors have been evaluated in clinical trials for R/R MM patients.
- Cardiotoxicity and other adverse effects are significant barriers to clinical application.
Conclusions:
- MCL1 inhibition is a critical therapeutic strategy for overcoming drug resistance in MM.
- Despite progress, adverse effects, particularly cardiotoxicity, remain a challenge for MCL1 inhibitors.
- Continued research into novel MCL1 inhibitors and strategies to mitigate side effects is essential for effective MM treatment.
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