5FC4

Mcl-1 complexed with small molecule inhibitor

Summary for 5FC4

• Entry DOI: 10.2210/pdb5fc4/pdb
• Related: 4ZBF
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, 6-chloranyl-~{N}-methylsulfonyl-3-(3-naphthalen-1-yloxypropyl)-1~{H}-indole-2-carboxamide, 2-[5-[1,1,2,2-tetrakis(fluoranyl)ethyl]-1~{H}-pyrazol-3-yl]phenol, ... (4 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: 1
• Total formula weight: 18134.40

Authors

Zhao, B. (deposition date: 2015-12-14, 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

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: 26878343
DOI: 10.1021/acs.jmedchem.5b01660

Experimental method

X-RAY DIFFRACTION (1.5 Å)