Action Mechanism of a Mcl-1 Inhibitor AZD5991
Posted On 2019-03-29
Apoptosis is a highly regulated program of cell death. Apoptosis occurs in multicellular organisms. Mcl-1 plays an important role in apoptosis. Mechanically, Mcl-1 promotes cell survival by preventing induction of apoptosis in many cancers. In addition, Mcl-1 is a member of the Bcl-2 family of proteins. In contrast to other Bcl-2 proteins, Mcl-1 has a large unstructured amino-terminus core. The core contains multiple phosphorylation, ubiquitination and caspase cleavage sites. These sites tightly control Mcl-1’s short protein half-life (1-4 h), fine-tuning its activity in response to pro-apoptotic and anti-apoptotic stimuli.
MCL-1 is within one of the most frequently amplified gene regions in human cancers. Morever, Mcl-1 expression often associates with resistance to cytotoxic agents and relapse in patients. Interestingly, high expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies. Importantly, several tumor types are dependent on Mcl-1, in particular multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia, B-cell acute lymphoblastic leukemia, hepatocellular carcinoma, and certain non-small cell lung cancers.
AZD5991 is a novel designed macrocyclic molecule with high selectivity and affinity for Mcl-1. In vitro, AZD5991 kills MM cells. Additionally, AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells. AZD5991 reduces the levels of Mcl-1 protein in AZD5991-sensitive but not in AZD5991-resistant MM cell lines. In vivo, AZD5991 exhibits potent anti-tumor efficacy in multiple myeloma models. AZD5991 shows potent anti-tumor activity with complete (100%) tumor regression (TR) in several multiple myeloma and acute myeloid leukemia models after a single tolerated intravenous dose. In conclusion, AZD5991 is a direct Mcl-1 inhibitor with high selectivity versus other Bcl-2 family proteins. AZD5991 has entered in clinical trial for evaluation in patients with hematological malignancies.