Recent Advances in the Development of Selective Mcl-1 Inhibitors for the Treatment of Cancer (2017-Present).

Abstract

Myeloid cell leukemia-1 (Mcl-1) protein, as a critical pro-survival member of the B-cell lymphoma 2 (Bcl-2) protein family, plays an important role in apoptosis, carcinogenesis and resistance to chemotherapies. Hence, potently and selectively inhibiting Mcl-1 to induce apoptosis has become a widely accepted anticancer strategy. This review intends to provide a comprehensive overview of patents and primary literature, published from 2017 to present, on small molecule Mcl-1 inhibitors with various scaffolds. By analyzing the modes of compound-protein interactions, the similarities and differences of those structures are discussed, which could provide guidance for future drug design. The primary accesses for patent searching are SciFinder and Espacenet®. Besides the data disclosed in patents, some results published in the follow-up research papers will be included in this review. The review covers dozens of patents on Mcl-1 inhibitors in the past three years, and the scaffolds of compounds are mainly divided into indole scaffolds and non-indole scaffolds. The compounds described here are compared with the relevant inhibitors disclosed in previous patents, and representative compounds, especially those launched in clinical trials, are emphasized in this review. For most of the compounds in these patents, analyses of the binding affinity to Mcl-1 and studies in multiple cell lines were conducted, wherein some compounds were tested in preclinical cancer models or were included in other biological studies. Some compounds showed promising results and potential for further study.