Saga of MCL1 inhibitors in multiple myeloma

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.