Advancements in MCL1 Inhibition: The Emergence of AMG 397 as an Oral Therapeutic

MCL1 inhibitors are a novel class of therapeutics that target the interaction between MCL1 and pro-apoptotic BCL-2 family members, with several undergoing clinical trials. However, current MCL1 inhibitors are administered intravenously, prompting the development of AMG 397, the first orally administered MCL1 inhibitor.

The development of AMG 397 was driven by the need for an orally bioavailable inhibitor with improved potency and pharmacokinetic properties over AMG 176, a compound in Phase I clinical development. The discovery process leveraged the two distinct conformations of AMG 176 when bound to MCL1. Using a structure-guided and ligand-based design approach, the team developed AM-3106, which showed significantly improved cell-based potency. Further optimization led to AMG 397, exhibiting high affinity for MCL1 and selectively disrupting the MCL1-BIM interaction.

In cellular studies, AMG 397 rapidly increased Caspase-3/7 activity and induced a committed step towards apoptosis, suggesting the potential for discontinuous dosing schedules. Hematologic malignancy cell lines, including AML, multiple myeloma, and DLBCL, showed high sensitivity to AMG 397. In vivo studies demonstrated that oral administration of AMG 397 led to sustained increases in activated BAK and cleaved Caspase-3 and PARP in OPM2 xenografts. Discontinuous dosing schedules resulted in significant tumor regressions, with a high rate of tumor-free mice at the study's end.

Additionally, AMG 397 was tested in an orthotopic model of AML, showing substantial tumor growth inhibition and regression at various doses. The compound was also effective in combination with venetoclax, demonstrating potential synergistic effects.

In summary, AMG 397 represents a significant advancement as a potent, selective, and orally bioavailable MCL1 inhibitor, with promising preclinical results supporting its potential in treating hematologic malignancies. The findings from the study provide a strong basis for further investigation and development of AMG 397 as a therapeutic agent.