School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, China().
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, China.
Expert Opin Ther Pat. 2023 Jan-Jun;33(5):371-383. doi: 10.1080/13543776.2023.2219394. Epub 2023 Jun 14.
Myeloid leukemia 1 (Mcl-1), an antiapoptotic protein of the Bcl-2 family, is an attractive target for cancer therapy. In recent years, significant progress has been made with regard to Mcl-1 inhibitors, leading to the generation of highly potent Mcl-1 inhibitors that have entered clinical trials.
This review provides an overview of the patent literature between 2020 and 2022 -covering inhibitors, antibody-drug conjugate (ADC), and proteolysis targeting chimera (PROTAC) of Mcl1.
Despite the great success of Mcl-1 inhibitor development, the on-target toxicity to heart indicated that the BH3 mimetic Mcl-1 inhibitors could have a limited therapeutic window.Drug combinations of Mcl-1 inhibitors with targeted therapies or chemotherapies may improve safety as they may reduce the dose of Mcl-1 inhibitors. Alternatively, some technologies like ADC and PROTACS could also be utilized to improve the therapeutic window. We envision a precision medicine platform like BH3 profiling or single-molecule pull-down and co-immunoprecipitation platform will enable the tailored use of Mcl-1 inhibitors utilizing the unique molecular information of individual patients.
髓性白血病 1（Mcl-1）是 Bcl-2 家族的一种抗凋亡蛋白，是癌症治疗的一个有吸引力的靶点。近年来，Mcl-1 抑制剂取得了重大进展，产生了进入临床试验的高活性 Mcl-1 抑制剂。
本综述概述了 2020 年至 2022 年期间的专利文献，涵盖了 Mcl1 的抑制剂、抗体药物偶联物（ADC）和蛋白水解靶向嵌合体（PROTAC）。
尽管 Mcl-1 抑制剂的开发取得了巨大成功，但对心脏的靶向毒性表明，BH3 模拟 Mcl-1 抑制剂的治疗窗口可能有限。Mcl-1 抑制剂与靶向治疗或化疗药物的联合用药可能会提高安全性，因为它们可能会降低 Mcl-1 抑制剂的剂量。或者，一些技术，如 ADC 和 PROTACS，也可以用于提高治疗窗口。我们设想 BH3 分析或单分子下拉和共免疫沉淀平台等精准医学平台将能够利用个体患者的独特分子信息，定制 Mcl-1 抑制剂的使用。
