Recent advances of small-molecule Mcl-1 inhibitors or degraders as promising anti-cancer agents (2018-present).

The B-cell lymphoma protein 2 (Bcl-2) family functions as a tripartite switch for cell death, meticulously modulating the intrinsic apoptosis pathway in response to diverse cellular signaling stresses via protein-protein interactions. As a key and unique member, myeloid cell leukemia-1 (Mcl-1) is crucial for the regulation of mitochondrial function within the intrinsic apoptotic pathway. Mcl-1 is overexpressed in numerous hematological malignancies as well as solid tumors, closely associated to tumor development, unsatisfactory prognosis, and resistance to chemotherapy. Consequently, it represents a promising therapeutic target in cancer treatment. In 2018, we reviewed the advances of small-molecule Mcl-1 inhibitors from 2012 to 2017. This review aims to summarize the updated advances of small-molecule Mcl-1 inhibitors (according to their core scaffolds) or degraders as promising anti-cancer agents (2018-present). Furthermore, the corresponding structure-activity relationships (SARs) of most compounds are also provided. Additionally, the co-crystal structures of some potent compounds in complex with Mcl-1 protein are also elucidated. This review is expected to provide valuable insights for medicinal chemists engaged in developing more effective small-molecule inhibitors or degraders targeting Mcl-1.