5FDR
Mcl-1 complexed with small molecule inhibitor
Summary for 5FDR
| Entry DOI | 10.2210/pdb5fdr/pdb |
| Related | 4HW2 |
| Descriptor | Induced myeloid leukemia cell differentiation protein Mcl-1, 5-[[6-chloranyl-3-[3-(4-chloranyl-3,5-dimethyl-phenoxy)propyl]-7-(3,5-dimethyl-1~{H}-pyrazol-4-yl)-1~{H}-indol-2-yl]carbonylsulfamoyl]furan-2-carboxylic acid (2 entities in total) |
| Functional Keywords | mcl-1, inhibitor, apoptosis-apoptosis inhibitor complex, apoptosis/apoptosis inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 74499.62 |
| Authors | Zhao, B. (deposition date: 2015-12-16, release date: 2016-03-02, Last modification date: 2023-09-27) |
| Primary citation | Pelz, N.F.,Bian, Z.,Zhao, B.,Shaw, S.,Tarr, J.C.,Belmar, J.,Gregg, C.,Camper, D.V.,Goodwin, C.M.,Arnold, A.L.,Sensintaffar, J.L.,Friberg, A.,Rossanese, O.W.,Lee, T.,Olejniczak, E.T.,Fesik, S.W. Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods. J.Med.Chem., 59:2054-2066, 2016 Cited by PubMed Abstract: Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization. PubMed: 26878343DOI: 10.1021/acs.jmedchem.5b01660 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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