AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies

Abstract

The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the signifi cant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the fi rst selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.

BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines

“…However, S63845, AMG 176, and possibly other MCL-1 inhibitors, have a weaker affinity for mouse, compared with human MCL-1 Kotschy et al, 2016). The recent development of two independent humanized MCL-1 mouse strains has permitted more accurate evaluations of the therapeutic potential of MCL-1 inhibitors and showed that, despite further pronounced effects on normal cells, a therapeutic window should be achievable (Brennan et al, 2018;Caenepeel et al, 2018).…”

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

“…Outstanding progress has been recently made in the discovery of selective and potent MCL-1 BH3 mimetics and several compounds are currently investigated in phase 1 clinical trials in mature B-cell malignancies ( Table 4). Despite the particular chemical features of each compound, they all exhibit a high specificity for MCL-1 and were reported to induce apoptosis in MM, MCL, and CLL pre-clinical studies [66][67][68]. It is notable that the addiction to MCL-1 of primary cells from MM patients at relapse is increased compared to those at diagnosis [57].…”

BCL-XL is essential for the protection from secondary anemia caused by radiation-induced fatal kidney damage

“…This reveals that genetic irreversible loss of Bcl-x has more severe consequences than pharmacological inhibition of BCL-XL for a defined period. This conclusion is reminiscent of the findings from investigations comparing the impact of genetic loss of pro-survival MCL-1 vs treatment of mice for a defined period with an MCL-1 specific BH3mimetic drug (Caenepeel et al, 2018;Kotschy et al, 2016). These and other studies (Brennan et al, 2018;Brinkmann et al, 2017) suggest that it may be possible to establish therapeutic windows for combination treatment using BH3-mimetic drugs and standard chemotherapy or radiation.…”