Discovery of Potent Myeloid Cell Leukemia‑1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer

• Published in: Journal of medicinal chemistry 2019-04, Vol.62 (8), p.3971-3988
• Main Authors: Lee, Taekyu, Christov, Plamen P, Shaw, Subrata, Tarr, James C, Zhao, Bin, Veerasamy, Nagarathanam, Jeon, Kyu Ok, Mills, Jonathan J, Bian, Zhiguo, Sensintaffar, John L, Arnold, Allison L, Fogarty, Stuart A, Perry, Evan, Ramsey, Haley E, Cook, Rebecca S, Hollingshead, Melinda, Davis Millin, Myrtle, Lee, Kyung-min, Koss, Brian, Budhraja, Amit, Opferman, Joseph T, Kim, Kwangho, Arteaga, Carlos L, Moore, William J, Olejniczak, Edward T, Savona, Michael R, Fesik, Stephen W
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Azepines - chemistry; Binding Sites; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Cells; Crystallography, X-Ray; Drug Evaluation, Preclinical; Female; Humans; Inhibitors; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Dynamics Simulation; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Neoplasms - drug therapy; Neoplasms - pathology; Protein Structure, Tertiary; Rodent models; Screening assays; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01991

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.