Premium
Discovery and biological characterization of potent myeloid cell leukemia‐1 inhibitors
Author(s) -
Lee Taekyu,
Bian Zhiguo,
Zhao Bin,
Hogdal Leah J.,
Sensintaffar John L.,
Goodwin Craig M.,
Belmar Johannes,
Shaw Subrata,
Tarr James C.,
Veerasamy Nagarathanam,
Matulis Shan M.,
Koss Brian,
Fischer Melissa A.,
Arnold Allison L.,
Camper DeMarco V.,
Browning Carrie F.,
Rossanese Olivia W.,
Budhraja Amit,
Opferman Joseph,
Boise Lawrence H.,
Savona Michael R.,
Letai Anthony,
Olejniczak Edward T.,
Fesik Stephen W.
Publication year - 2017
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12497
Subject(s) - myeloid leukemia , cancer research , leukemia , apoptosis , gene knockdown , cancer , cancer cell , myeloid , rna interference , chemistry , biology , biochemistry , immunology , gene , genetics , rna
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 RNA i 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 .