4OQ6

Crystal Structure of Human MCL-1 Bound to Inhibitor 4-hydroxy-4'-propylbiphenyl-3-carboxylic acid

Summary for 4OQ6

• Entry DOI: 10.2210/pdb4oq6/pdb
• Related: 4OQ5
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, 4-hydroxy-4'-propylbiphenyl-3-carboxylic acid (3 entities in total)
• Functional Keywords: apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass membrane protein (Potential): Q07820
• Total number of polymer chains: 2
• Total formula weight: 36277.37

Authors

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. (deposition date: 2014-02-07, release date: 2014-03-12, Last modification date: 2024-02-28)

Primary citation

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.
Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein.
Bioorg.Med.Chem.Lett., 24:1484-1488, 2014

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.

PubMed: 24582986
DOI: 10.1016/j.bmcl.2014.02.010

Experimental method

X-RAY DIFFRACTION (1.81 Å)