6BW8

Mcl-1 complexed with small molecules

Summary for 6BW8

• Entry DOI: 10.2210/pdb6bw8/pdb
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, 7-{8-chloro-11-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl}-1-methyl-1H-indole-3-carboxylic acid (2 entities in total)
• Functional Keywords: mcl-1 inhibitor, cancer, structure-based design, drug discovery, apoptosis
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 74768.24

Authors

Zhao, B. (deposition date: 2017-12-14, release date: 2018-01-31, Last modification date: 2023-10-04)

Primary citation

Shaw, S.,Bian, Z.,Zhao, B.,Tarr, J.C.,Veerasamy, N.,Jeon, K.O.,Belmar, J.,Arnold, A.L.,Fogarty, S.A.,Perry, E.,Sensintaffar, J.L.,Camper, D.V.,Rossanese, O.W.,Lee, T.,Olejniczak, E.T.,Fesik, S.W.
Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design.
J. Med. Chem., 61:2410-2421, 2018

PubMed Abstract: Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.

PubMed: 29323899
DOI: 10.1021/acs.jmedchem.7b01155

Experimental method

X-RAY DIFFRACTION (2.9 Å)