Structure-Based Design, Synthesis and Evaluation of Novel and Selective Small-Molecule Inhibitors of the Anti-Apoptotic Protein Mcl-1.

[摘要] The mitochondrial pathway to apoptosis is regulated through the protein-protein interactions of pro- and anti-apoptotic members of Bcl-2 family proteins. Overexpression of the anti-apoptotic members such as Mcl-1, Bcl-2 and Bcl-XL has been observed in cancer, contributing to chemoresistance and aberrant survival. Pro-apoptotic BH3-only proteins normally serve to suppress the anti-apoptotic members. Thus, small molecules mimicking the function of BH3-only proteins have been developed and exhibited anti-cancer activity. Notably, ABT-737, a selective and potent Bcl-2/Bcl-XL inhibitor, has shown to be highly efficacious at inducing apoptosis in Bcl-2/Bcl-XL-dependent cancers, but it is not effective in cancer cells with high Mcl-1 levels. Therefore, Mcl-1 represents an attractive target for the development of a new class of anti-cancer therapy that would be synergistic with ABT-737.High throughput screening (HTS) approaches were utilized and several small molecules capable of binding to Mcl-1 were identified. To improve the output of the HTS hits, as well as to incorporate structure-based knowledge, in silico screening of identified hits was integrated and the most promising inhibitors were selected. In this work, two classes of small-molecule Mcl-1 inhibitors were developed based on two HTS leads, 59 bearing a hydroxynaphthalenylsulfonamide and 38 with a 1H-pyrazolo[3,4-b]pyridine scaffolds. Employing structure-based design in conjunction with protein NMR spectroscopy, new analogs were designed, synthesized and SARs were established. Two potent inhibitors, 21 from 59 class and 8 from 38 class, were developed exhibiting 9- and 12-fold improvement over their respective HTS leads. Both analogs exhibited selective inhibition of Mcl-1 over other anti-apoptotic proteins. NMR studies mapped the binding sites of 21 and 8 to the BH3-binding groove of Mcl-1. Analog 21 was further characterized in cell-based assays and caused cell death in Mcl-1-dependant cancer cell lines through a Bak/Bax-dependent mechanism and activation of caspase-3. Additionally, another potent analog from 59 series, 10, was used as a chemical tool to validate Mcl-1 as a potential therapeutic target in pancreatic cancer. This work provides further understanding in the development of selective Mcl-1 inhibitors and lays a foundation for the design of more potent inhibitors which can advance the field of targeted therapies for Mcl-1-driven cancers.

[发布机构] University of Michigan

[效力级别] Medicinal Chemistry

[关键词] Anti-apoptotic Mcl-1;Medicinal Chemistry;Protein-protein Interaction Inhibitor;Cancer;Protein NMR Spectroscopy;Structure-activity Relationship;Biological Chemistry;Chemistry;Science;Medicinal Chemistry