4ZBI

Mcl-1 complexed with small molecules

Summary for 4ZBI

• Entry DOI: 10.2210/pdb4zbi/pdb
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, 1-[3-(naphthalen-1-yloxy)propyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid (3 entities in total)
• Functional Keywords: inhibitor, complex, apoptosis-apoptosis inhibitor complex, apoptosis/apoptosis inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 12
• Total formula weight: 218828.83

Authors

Zhao, B. (deposition date: 2015-04-14, release date: 2015-04-29, Last modification date: 2024-03-06)

Primary citation

Burke, J.P.,Bian, Z.,Shaw, S.,Zhao, B.,Goodwin, C.M.,Belmar, J.,Browning, C.F.,Vigil, D.,Friberg, A.,Camper, D.V.,Rossanese, O.W.,Lee, T.,Olejniczak, E.T.,Fesik, S.W.
Discovery of tricyclic indoles that potently inhibit mcl-1 using fragment-based methods and structure-based design.
J.Med.Chem., 58:3794-3805, 2015

PubMed Abstract: Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.

PubMed: 25844895
DOI: 10.1021/jm501984f

Experimental method

X-RAY DIFFRACTION (2.5 Å)