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

Biochemistry
Bin ZhaoStephen W Fesik

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, we tested ...Continue Reading

References

Jul 18, 2002·Nature Reviews. Drug Discovery·John C Reed
Jan 28, 2004·Cell·Nika N Danial, Stanley J Korsmeyer
Mar 5, 2004·Biochimica Et Biophysica Acta·Andrew M PetrosStephen W Fesik
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Aug 25, 2004·Analytical Biochemistry·Zaneta Nikolovska-ColeskaShaomeng Wang
Feb 27, 2007·Oncogene·J M Adams, S Cory
Mar 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Peter E CzabotarPeter M Colman
Jun 11, 2008·Methods in Molecular Biology·Peter H ZwartPaul D Adams
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 19, 2010·Nature·Rameen BeroukhimMatthew Meyerson
Jun 15, 2010·FEBS Letters·Luke W ThomasSteven W Edwards
Jun 22, 2010·Nature Chemical Biology·Michelle L StewartLoren D Walensky
Jan 14, 2012·Journal of Medicinal Chemistry·David J HugginsBruce Tidor
Dec 21, 2013·Nature Reviews. Molecular Cell Biology·Peter E CzabotarJerry M Adams
Mar 4, 2014·Bioorganic & Medicinal Chemistry Letters·Andrew M PetrosChaohong Sun
Feb 14, 2015·Journal of Medicinal Chemistry·Milan BrunckoAndrew J Souers
May 9, 2015·Cell Death and Differentiation·A R D Delbridge, A Strasser
Oct 28, 2016·Nature·András KotschyOlivier Geneste
Feb 18, 2017·Nature Reviews. Drug Discovery·Avi AshkenaziAndrew J Souers

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