Displacement of FITC-Bak-BH3 peptide probe from N-terminal His-tagged human Mcl-1 (172 to 327 residues) expressed in Escherichia coli BL21(DE3) after 1.5 hrs by FPA based competition assay
- Deposit:2018-09-05
- Modify:2022-08-30
Title: Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.
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.
Compounds with activity <= 10uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.
Journal: J Med Chem
Year: 2016
Volume: 59
Issue: 5
First Page: 2054
Last Page: 2066
DOI: 10.1021/acs.jmedchem.5b01660
Target ChEMBL ID: CHEMBL4361
ChEMBL Target Name: Induced myeloid leukemia cell differentiation protein Mcl-1
ChEMBL Target Type: SINGLE PROTEIN - Target is a single protein chain
Relationship Type: D - Direct protein target assigned
Confidence: Direct single protein target assigned
- PubChem
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