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FEBS Lett. 2017 Jan;591(1):240-251. doi: 10.1002/1873-3468.12497. Epub 2016 Dec 19.

Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

Author information

1
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
2
Department of Hematology and Medical Oncology and The Winship Cancer Institute, Emory University, Atlanta, GA, USA.
3
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
4
Vanderbilt University Medical Center, Nashville, TN, USA.
5
Department of Adult Oncology, The Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

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.

KEYWORDS:

apoptosis; cancer; drug discovery; myeloid cell leukemia 1; structure-based drug design

PMID:
27878989
PMCID:
PMC5381274
DOI:
10.1002/1873-3468.12497
[Indexed for MEDLINE]
Free PMC Article

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