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

Authors

Taekyu Lee, Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.
Plamen P. Christov, Chemical Synthesis Core, Vanderbilt Institute of Chemical Biology , Vanderbilt University , Nashville , Tennessee 37232 , United States.
Subrata Shaw, Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.
James C. Tarr, Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.
Bin Zhao, Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.Follow
Nagarathanam Veerasamy, Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.
Kyu Ok Jeon, Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.
Jonathan J. Mills, Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.
Zhiguo Bian, Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.

Abstract

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.

Publication Title

Journal of medicinal chemistry

Recommended Citation

Lee, T., Christov, P. P., Shaw, S., Tarr, J. C., Zhao, B., Veerasamy, N., Jeon, K. O., Mills, J. J., & Bian, Z. (2019). Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer. Journal of medicinal chemistry, 62 (8), 3971-3988. https://doi.org/10.1021/acs.jmedchem.8b01991