Abstract
Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).
Highlights
Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers
Several tumor types have been described as being dependent on Mcl-1, in particular multiple myeloma (MM)[11], acute myeloid leukemia (AML)[12], chronic myeloid leukemia[13], B-cell acute lymphoblastic leukemia[14], hepatocellular carcinoma[15], and certain non-small cell lung cancers[16]
One avenue began with analysis of a series of indole-2-carboxylic acids which have been reported by others[25,26,27]. Investigating one such literature compound, 1, we were able to obtain a co-crystal structure in complex with Mcl-1 (Fig. 1a)
Summary
Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683). The long shallow hydrophobic protein–protein interaction interface has proven challenging to drug with a small molecule and while many inhibitors have been reported in the literature and even in clinical trials, off-target effects have been shown to drive phenotypic activity for many compounds[22]
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