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

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. In conclusion, 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.

Authors:
ORCiD logo [1];  [1];  [2];  [1];  [1];  [1];  [1]
  1. Vanderbilt Univ., Nashville, TN (United States)
  2. Vanderbilt Univ., Nashville, TN (United States); AbbVie, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); Leidos Biomed Prime; NCI SPORE
OSTI Identifier:
1368271
Alternate Identifier(s):
OSTI ID: 1413840
Grant/Contract Number:  
AC02-06CH11357; HHSN261200800001E; P50CA098131
Resource Type:
Accepted Manuscript
Journal Name:
Bioorganic and Medicinal Chemistry
Additional Journal Information:
Journal Volume: 25; Journal Issue: 12; Journal ID: ISSN 0968-0896
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Human Serum Albumin; Free fraction; Apoptosis; Cancer; Mcl-1; Drug discovery

Citation Formats

Zhao, Bin, Sensintaffar, John, Bian, Zhiguo, Belmar, Johannes, Lee, Taekyu, Olejniczak, Edward T., and Fesik, Stephen W. Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin. United States: N. p., 2017. Web. doi:10.1016/j.bmc.2017.03.060.
Zhao, Bin, Sensintaffar, John, Bian, Zhiguo, Belmar, Johannes, Lee, Taekyu, Olejniczak, Edward T., & Fesik, Stephen W. Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin. United States. doi:10.1016/j.bmc.2017.03.060.
Zhao, Bin, Sensintaffar, John, Bian, Zhiguo, Belmar, Johannes, Lee, Taekyu, Olejniczak, Edward T., and Fesik, Stephen W. Mon . "Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin". United States. doi:10.1016/j.bmc.2017.03.060. https://www.osti.gov/servlets/purl/1368271.
@article{osti_1368271,
title = {Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin},
author = {Zhao, Bin and Sensintaffar, John and Bian, Zhiguo and Belmar, Johannes and Lee, Taekyu and Olejniczak, Edward T. and Fesik, Stephen W.},
abstractNote = {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. In conclusion, 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.},
doi = {10.1016/j.bmc.2017.03.060},
journal = {Bioorganic and Medicinal Chemistry},
number = 12,
volume = 25,
place = {United States},
year = {2017},
month = {5}
}

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