Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.
LifeMine Therapeutics, Cambridge, MA, USA.
Nat Commun. 2018 Dec 17;9(1):5341. doi: 10.1038/s41467-018-07551-w.
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).
Mcl-1 是 Bcl-2 家族蛋白的成员，通过防止许多癌症中的细胞凋亡诱导来促进细胞存活。Mcl-1 的高表达导致肿瘤发生和对癌症治疗的耐药性，突出了 Mcl-1 抑制剂作为抗癌药物的潜力。在这里，我们描述了 AZD5991，这是一种合理设计的大环分子，对 Mcl-1 具有高选择性和亲和力，目前正在临床开发中。我们的研究表明，AZD5991 直接与 Mcl-1 结合，并通过激活 Bak 依赖性线粒体凋亡途径，在癌细胞中迅速诱导凋亡，尤其是骨髓瘤和急性髓系白血病。AZD5991 在体内具有很强的抗肿瘤活性，在多发性骨髓瘤和急性髓系白血病的几种模型中单用或与硼替佐米或 venetoclax 联合使用一次耐受剂量后，可完全消退肿瘤。基于这些有希望的数据，已经启动了一项 I 期临床试验，以评估 AZD5991 在血液恶性肿瘤患者中的疗效（NCT03218683）。
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