The B-cell lymphoma-2 (BCL-2) family of proteins, including myeloid cell leukemia 1 (MCL-1), are key regulators of the mitochondrial apoptotic pathway. Dysregulation of this family of proteins is frequently responsible for evasion of apoptosis, a hallmark of cancer. Therapeutic interventions to MCL-1's oncogenic activity, targeting key protein-protein interactions between MCL-1 and the BH3 domain containing pro-apoptotic BCL-2 family members, has come of age in the past few years following decades of research. Several development candidates, all administered intravenously, have entered clinical trials including AMG 176, which is currently in Phase I clinical development for hematologic malignancies. Here we disclose AMG 397, the first orally administered MCL-1 inhibitor in clinical development. The pursuit of an orally bioavailable MCL-1 inhibitor with an acceptable human clinical dose required improvements in both potency and pharmacokinetic properties. One approach was to minimize the large cell shifts attributable to the negative charge ensuing from the acidic acyl sulfonamide moiety under physiological conditions. Introduction of basic functional groups improved cellular activity, credited to their ability to offset the negative charge of the acidic group and improve cell membrane penetration. However, these changes did little to enhance binding affinity or improve pharmacokinetic (PK) properties. The X-ray co-crystal structure revealed two conformations in AMG 176 bound to MCL-1. Subsequent conformational analysis indicated a significant difference in energy between the two conformations, with the conformer higher in energy determined to be also higher in binding affinity. Thus, a structure-guided approach coupled with ligand-based design, aiming to stabilize the more active conformation and lower cell shifts, led to compounds with significantly improved binding affinity and cellular potency, and yet promising PK properties. Further optimizations and refinements in potency and PK parameters culminated in the discovery of AMG 397. AMG 397 exhibited excellent affinity to MCL-1 and potent on-mechanism cell killing activity. AMG 397 is also selective against other pro-survival BCL-2 family proteins and competitive for binding to MCL-1 with pro-apoptotic BCL-2 family members. This presentation will describe the discovery highlights and preclinical evaluation of AMG 397.

Interdiction at a protein-protein interface: Discovery of AMG 397, a potent, selective and orally efficacious MCL-1 inhibitor

ACS Fall 2020 Virtual Meeting

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