| Literature DB >> 27878989 |
Taekyu Lee1, Zhiguo Bian1, Bin Zhao1, Leah J Hogdal1, John L Sensintaffar1, Craig M Goodwin1, Johannes Belmar1, Subrata Shaw1, James C Tarr1, Nagarathanam Veerasamy1, Shannon M Matulis2, Brian Koss3, Melissa A Fischer4, Allison L Arnold1, DeMarco V Camper1, Carrie F Browning1, Olivia W Rossanese1, Amit Budhraja3, Joseph Opferman3, Lawrence H Boise2, Michael R Savona4, Anthony Letai5, Edward T Olejniczak1, Stephen W Fesik1.
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. PDB ID CODES: Comp. 2: 5IEZ; Comp. 5: 5IF4.Entities:
Keywords: apoptosis; cancer; drug discovery; myeloid cell leukemia 1; structure-based drug design
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Year: 2016 PMID： 27878989 PMCID： PMC5381274 DOI： 10.1002/1873-3468.12497
Source DB: PubMed Journal: FEBS Lett ISSN： 0014-5793 Impact factor: 4.124