Abstract 2405: Inhibitor of apoptosis protein antagonists as novel targeted chemotherapeutic agents for acute myeloid leukemia

Abstract

Abstract Acute myeloid leukemia (AML) is a diverse collection of hematological cancers characterized by the bone marrow's excessive production of certain immature myeloid blood cells. The American Cancer Society estimated that there was ~11,000 deaths and ~21,500 new incidences of AML in the U.S. in 2019. While the various AML subtypes have differing prognoses, more than 30% of AML patients fail to enter complete remission upon standard chemotherapy regimens. Furthermore, most patients that do initially respond will relapse within 5 years in the absence of bone marrow transplantation (BMT). As such, the need for novel targets and drugs to treat this disease is a significant unmet medical need. This is especially true in patient populations unable to tolerate aggressive chemotherapy or where BMT is impossible or not recommended. The current standard of care (SOC) for AML has been the same for decades - various combinations of anthracyclines and nucleoside analogues are used as front line agents with debilitating toxicities. Recent evidence showing efficacy of Bcl2 family inhibitors in some leukemias prompted us to investigate whether antagonism of the inhibitor of apoptosis (IAP) proteins may be effective against AML. IAP proteins are involved in many processes including cell death, immunity, inflammation, cell cycle and migration, and are therefore promising targets for the development of cancer therapeutics. As the name suggests, IAP proteins play an important role in the control of apoptotic pathways and have been implicated in AML development and progression. It has been shown that IAPs are over-expressed in AML patient cells and high expression levels are linked to poor prognosis. Although Bcl2 family members only regulate mitochondrial apoptosis, IAPs modulate apoptotic signaling at multiple, and more distal, points suggesting a potential improvement in activity for drugs targeting them. We recently described the characterization and preliminary optimization of monovalent small molecule IAP antagonists. Here we show the design and synthesis of novel second generation bivalent IAP antagonists that kill AML cells much more potently than drugs currently undergoing clinical evaluation, while sparing healthy cells. Our data in leukemia cell lines and patient-derived AML samples using these novel, highly potent, IAP antagonists suggest that these small molecules may be effective as therapeutic agents. Citation Format: Darren Finlay, Nicole Bata, Allison Limpert, Dominik Heimann, Peter Teriete, Carol Burian, James Mason, Nicholas D. Cosford, Kristiina Vuori. Inhibitor of apoptosis protein antagonists as novel targeted chemotherapeutic agents for acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2405.