5IEZ

Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) inhibitors using Structure-Based Design

Summary for 5IEZ

• Entry DOI: 10.2210/pdb5iez/pdb
• Related: 5IF4
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, 3-({6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl}amino)benzoic acid (3 entities in total)
• Functional Keywords: myeloid cell leukemia-1, bcl-2, apoptosis, apoptosis-apoptosis inhibitor complex, apoptosis/apoptosis inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 74623.93

Authors

Zhao, B. (deposition date: 2016-02-25, release date: 2017-01-18, Last modification date: 2024-03-06)

Primary citation

Lee, T.,Bian, Z.,Zhao, B.,Hogdal, L.J.,Sensintaffar, J.L.,Goodwin, C.M.,Belmar, J.,Shaw, S.,Tarr, J.C.,Veerasamy, N.,Matulis, S.M.,Koss, B.,Fischer, M.A.,Arnold, A.L.,Camper, D.V.,Browning, C.F.,Rossanese, O.W.,Budhraja, A.,Opferman, J.,Boise, L.H.,Savona, M.R.,Letai, A.,Olejniczak, E.T.,Fesik, S.W.
Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.
FEBS Lett., 591:240-251, 2017

PubMed Abstract: Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors.

PubMed: 27878989
DOI: 10.1002/1873-3468.12497

Experimental method

X-RAY DIFFRACTION (2.6 Å)