Download MendeleyFragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein.
Petros, A.M., Swann, S.L., Song, D., Swinger, K., Park, C., Zhang, H., Wendt, M.D., Kunzer, A.R., Souers, A.J., Sun, C.(2014) Bioorg Med Chem Lett 24: 1484-1488
- PubMed: 24582986
- DOI: https://doi.org/10.1016/j.bmcl.2014.02.010
- Primary Citation of Related Structures:
4OQ5, 4OQ6 - PubMed Abstract:
Apoptosis is regulated by the BCL-2 family of proteins, which is comprised of both pro-death and pro-survival members. Evasion of apoptosis is a hallmark of malignant cells. One way in which cancer cells achieve this evasion is thru overexpression of the pro-survival members of the BCL-2 family. Overexpression of MCL-1, a pro-survival protein, has been shown to be a resistance factor for Navitoclax, a potent inhibitor of BCL-2 and BCL-XL. Here we describe the use of fragment screening methods and structural biology to drive the discovery of novel MCL-1 inhibitors from two distinct structural classes. Specifically, cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts.
Organizational Affiliation:
Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States. Electronic address: [email protected].
