tapotoclax (AMG 176)

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)...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.

The structural foundations for the design of MCL-1 inhibitors are revisited, the pharmacological profiles of the leading drugs (S63845, AZD5991, AMG 176) in advanced clinical development are summarized, and emerging strategies, such as combination therapies with inhibitors of anti-apoptotic proteins such as BCL-2, PROTAC strategies designed to degrade MCL-1, and reversible-binding chemotypes to maximize MCL-1 inhibition and minimize toxicity, are reviewed. The key to clinical success will be to carefully develop more intensive dosing regimens, rationally combine agents, and develop trial designs that prioritize the evaluation of new agents that maximize antitumor activity without the risk of off-target toxicities. Continued translational research and adaptive clinical trials are critical to fully realize the therapeutic potential of MCL-1 inhibition across various cancer contexts.

P1, N=141, Terminated, Amgen | Completed --> Terminated; sponsor decision, unrelated to safety

P1, N=7, Terminated, Amgen | Completed --> Terminated; Sponsor decision, unrelated to safety.

P1, N=142, Completed, Amgen | Active, not recruiting --> Completed

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms...Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors...Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.

P1, N=142, Active, not recruiting, Amgen | Trial primary completion date: Jan 2024 --> Sep 2024

P1, N=9, Completed, Amgen | Recruiting --> Completed | N=120 --> 9 | Trial completion date: Dec 2026 --> Dec 2023 | Trial primary completion date: Dec 2025 --> Dec 2023

P1, N=142, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting

P1, N=175, Recruiting, Amgen | Trial completion date: Mar 2025 --> Aug 2024

We devised a novel augmentation on the conventional CRISPR/Cas9 KO/DO screen utilizing two MCL cell lines (Jeko1, Z138) which were both resistant to apoptosis induced by VEN +/- ibrutinib (IBR)(Fig 1)...The screen method was repeated in Jeko1 cells using the MCL1 inhibitor AMG176 and BCL-XL inhibitor A1331853, and again yielded BCL2 as well as novel hits, including MARCH5 KO as a sensitizing hit to BCL-XL inhibition...Degron dTAG-mediated depletion of MARCH5 demonstrated synergy with venetoclax in MOLM13 (AML) and Z138 (MCL) cell lines, and enhanced in vitro killing of MOLM13 by VEN + azacytidine, and killing of Jeko1 and Z138 by VEN + IBR...MARCH5 depletion also sensitizes blood cancer cell lines to BCL-XL inhibition. Addition of MARCH5 depletion to VEN-combination treatment improved MCL and AML killing in vitro, and this target should be prioritized for accelerated drug development.

P1, N=120, Recruiting, Amgen | Trial completion date: Mar 2026 --> Dec 2026 | Trial primary completion date: Mar 2025 --> Dec 2025