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Title: Understanding the Species Selectivity of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors

Abstract

To test for on target toxicity of a new chemical entity, it is important to have comparable binding affinities of the compound in the target proteins from humans and the test species. To evaluate our myeloid cell leukemia-1 (Mcl-1) inhibitors, we tested them against rodent Mcl-1 and found a significant loss of binding affinity when compared to that seen with human Mcl-1. To understand the affinity loss, we used sequence alignments and structures of human Mcl-1/inhibitor complexes to identify the important differences in the amino acid sequences. One difference is human L246 (F226 in rat, F227 in mouse) in the ligand binding pocket. Mutating rat F226 to a Leu restores affinity, but the mouse F227L mutant still has a ligand affinity that is lower than that of human Mcl-1. Another mutation of mouse F267, located ~12 Å from the ligand pocket, to the human/rat cysteine, F267C, improved the affinity and combined with F227L resulted in a mutant mouse protein with a binding affinity similar to that of human Mcl-1. To help understand the structural components of the affinity loss, we obtained an X-ray structure of a mouse Mcl-1/inhibitor complex and identified how the residue changes reduced compound complementarity. Finally, wemore » tested Mcl-1 of other preclinical animal models (canine, monkey, rabbit, and ferret) that are identical to humans in terms of these two residues and found that their Mcl-1 bound our compounds with affinities comparable to that of human Mcl-1. Furthermore, these results have implications for understanding ligand selectivity for similar proteins and for the interpretation of preclinical toxicology studies with Mcl-1 inhibitors.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1]; ORCiD logo [1]
  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health
OSTI Identifier:
1478116
Grant/Contract Number:  
AC02-06CH11357; S10 RR026915; HHSN261200800001E; P50CA098131
Resource Type:
Accepted Manuscript
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 57; Journal Issue: 32; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; rodent models; peptides and proteins; inorganic compounds; ligands; Group 13 compounds

Citation Formats

Zhao, Bin, Arnold, Allison L., Coronel, Marcelle A., Lee, Joyce H., Lee, Taekyu, Olejniczak, Edward T., and Fesik, Stephen W. Understanding the Species Selectivity of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors. United States: N. p., 2018. Web. doi:10.1021/acs.biochem.8b00626.
Zhao, Bin, Arnold, Allison L., Coronel, Marcelle A., Lee, Joyce H., Lee, Taekyu, Olejniczak, Edward T., & Fesik, Stephen W. Understanding the Species Selectivity of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors. United States. https://doi.org/10.1021/acs.biochem.8b00626
Zhao, Bin, Arnold, Allison L., Coronel, Marcelle A., Lee, Joyce H., Lee, Taekyu, Olejniczak, Edward T., and Fesik, Stephen W. Mon . "Understanding the Species Selectivity of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors". United States. https://doi.org/10.1021/acs.biochem.8b00626. https://www.osti.gov/servlets/purl/1478116.
@article{osti_1478116,
title = {Understanding the Species Selectivity of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors},
author = {Zhao, Bin and Arnold, Allison L. and Coronel, Marcelle A. and Lee, Joyce H. and Lee, Taekyu and Olejniczak, Edward T. and Fesik, Stephen W.},
abstractNote = {To test for on target toxicity of a new chemical entity, it is important to have comparable binding affinities of the compound in the target proteins from humans and the test species. To evaluate our myeloid cell leukemia-1 (Mcl-1) inhibitors, we tested them against rodent Mcl-1 and found a significant loss of binding affinity when compared to that seen with human Mcl-1. To understand the affinity loss, we used sequence alignments and structures of human Mcl-1/inhibitor complexes to identify the important differences in the amino acid sequences. One difference is human L246 (F226 in rat, F227 in mouse) in the ligand binding pocket. Mutating rat F226 to a Leu restores affinity, but the mouse F227L mutant still has a ligand affinity that is lower than that of human Mcl-1. Another mutation of mouse F267, located ~12 Å from the ligand pocket, to the human/rat cysteine, F267C, improved the affinity and combined with F227L resulted in a mutant mouse protein with a binding affinity similar to that of human Mcl-1. To help understand the structural components of the affinity loss, we obtained an X-ray structure of a mouse Mcl-1/inhibitor complex and identified how the residue changes reduced compound complementarity. Finally, we tested Mcl-1 of other preclinical animal models (canine, monkey, rabbit, and ferret) that are identical to humans in terms of these two residues and found that their Mcl-1 bound our compounds with affinities comparable to that of human Mcl-1. Furthermore, these results have implications for understanding ligand selectivity for similar proteins and for the interpretation of preclinical toxicology studies with Mcl-1 inhibitors.},
doi = {10.1021/acs.biochem.8b00626},
journal = {Biochemistry},
number = 32,
volume = 57,
place = {United States},
year = {Mon Jul 16 00:00:00 EDT 2018},
month = {Mon Jul 16 00:00:00 EDT 2018}
}

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Works referencing / citing this record:

Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia
journal, December 2018