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Bioorg Med Chem. 2017 Jun 15;25(12):3087-3092. doi: 10.1016/j.bmc.2017.03.060. Epub 2017 Mar 29.

Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin.

Author information

1
Department of Biochemistry, Vanderbilt University, 2215 Garland Avenue, 607 Light Hall, Nashville, TN 37232-0146, USA.
2
Department of Biochemistry, Vanderbilt University, 2215 Garland Avenue, 607 Light Hall, Nashville, TN 37232-0146, USA. Electronic address: stephen.fesik@vanderbilt.edu.

Abstract

Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum. Here we describe the structure of a lead Mcl-1 inhibitor when bound to Human Serum Albumin (HSA). Unlike many acidic lipophilic compounds that bind to drug site 1 or 2, we found that this Mcl-1 inhibitor binds predominantly to drug site 3. Site 3 of HSA may be able to accommodate larger, more rigid compounds that do not fit into the smaller drug site 1 or 2. Structural studies of molecules that bind to this third site may provide insight into how some higher molecular weight compounds bind to albumin and could be used to aid in the design of compounds with reduced albumin binding.

KEYWORDS:

Apoptosis; Cancer; Drug discovery; Free fraction; Human Serum Albumin; Mcl-1

PMID:
28428041
PMCID:
PMC6690437
DOI:
10.1016/j.bmc.2017.03.060
[Indexed for MEDLINE]
Free PMC Article

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