Abstract DDT01-01: The discovery and preclinical characterization of AMG 176: A first-in-class Mcl-1 inhibitor in clinical development for multiple myeloma

Abstract

Abstract Mcl-1 is a prosurvival member of the Bcl-2 family of proteins, which regulate programmed cell death via protein-protein interactions between prosurvival and proapoptotic members of the family. A variety of studies have demonstrated that Mcl-1 is a key prosurvival factor for many human cancers, making it a highly desirable target for therapeutic intervention. However, targeting Mcl-1 to induce tumor cell death has been an exceptional challenge for the development of drug-like small molecule inhibitors due to the high-affinity interaction of Mcl-1 with proapoptotic binding partners and the lack of an obvious small molecule binding pocket. In this presentation we will describe the application of structural analysis and molecular modeling to the optimization of an HTS screening hit that culminated in the identification of a clinical candidate, AMG 176. In addition, we will present data demonstrating that AMG 176 is a potent, highly selective, and reversible Mcl-1 inhibitor. Mechanism-of-action studies revealed that AMG 176 induces a rapid and irreversible commitment to apoptosis in tumor cells via the disruption of protein-protein interactions with proapoptotic members of the Bcl-2 family. Furthermore, the extensive profiling of a large and diverse tumor cell line panel revealed that lines derived from hematologic malignancies, such as multiple myeloma, acute myeloid leukemia, and non-Hodgkin lymphoma, are particularly sensitive to Mcl-1 inhibition with the expression of Bcl-xL inversely correlating with response. In addition, cell line profiling data revealed an activity profile distinct from a selective Bcl-2 inhibitor, further underscoring the unique therapeutic opportunity for an Mcl-1 inhibitor. Synergistic combinations were identified with therapies selectively targeting Bcl-2, the MAPK pathway, and proteasome inhibitors. In vivo, AMG 176 demonstrated robust inhibition of tumor xenograft growth with a clear PK/PD relationship, exhibiting on-mechanism activity as measured by Bak and caspase activation on a discontinuous dosing schedule of once or twice weekly. An ongoing phase 1 clinical trial is currently evaluating AMG 176 in multiple myeloma. Citation Format: Paul E. Hughes. The discovery and preclinical characterization of AMG 176: A first-in-class Mcl-1 inhibitor in clinical development for multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-01. doi:10.1158/1538-7445.AM2017-DDT01-01