A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy

Chemical Science
Fereidoon DaryaeePeter J Tonge

Abstract

Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug discovery. Previously we described a mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model that used drug-target binding kinetics to successfully predict the in vivo efficacy of antibacterial compounds in models of Pseudomonas aeruginosa and Staphylococcus aureus infection. In the present work we extend this model to quantitatively correlate the engagement of Bruton's tyrosine kinase (Btk) by the covalent inhibitor CC-292 with the ability of this compound to reduce ankle swelling in an animal model of arthritis. The modeling studies include the rate of Btk turnover and reveal the vulnerability of Btk to engagement by CC-292.

References

Jun 8, 2004·Arthritis Research & Therapy·Gregg J Silverman, Dennis A Carson
Aug 5, 2006·Nature Reviews. Drug Discovery·Robert A CopelandThomas D Meek
Aug 22, 2006·Autoimmunity Reviews·Lorena Martinez-GamboaThomas Dörner
Oct 13, 2006·Clinical and Experimental Immunology·L Marinova-MutafchievaR O Williams
Sep 2, 2008·Pharmaceutical Research·Justin C EarpWilliam J Jusko
Oct 29, 2008·Journal of Proteome Research·Mary K DohertyRobert J Beynon
Jul 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Lee A HonigbergJoseph J Buggy
Jul 29, 2010·Current Opinion in Chemical Biology·Hao Lu, Peter J Tonge
Sep 2, 2010·Cell Research·Hongbiao HuangJinbao Liu
Nov 30, 2010·Nature Chemical Biology·Julie A Di PaoloKevin S Currie
Mar 24, 2011·Current Opinion in Rheumatology·Faye A H Cooles, John D Isaacs
May 28, 2013·The Journal of Pharmacology and Experimental Therapeutics·Erica K EvansWilliam F Westlin
Apr 12, 2014·Drug Discovery Today·Jennifer A Whang, Betty Y Chang
Aug 19, 2014·Inflammation·Ahmet KaratasAhmet Isik
Jan 22, 2015·Translational Research : the Journal of Laboratory and Clinical Medicine·Ying WangXiaoyan Shen
Apr 22, 2015·Nature Chemical Biology·Grant K WalkupStewart L Fisher
May 26, 2015·Nature Chemical Biology·J Michael BradshawJack Taunton
May 26, 2015·Nature Chemical Biology·Robert A Copeland
Dec 19, 2015·Nature Reviews. Drug Discovery·Robert A Copeland

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Citations

Jun 24, 2017·ACS Chemical Neuroscience·Peter J Tonge
Aug 7, 2021·RSC Medicinal Chemistry·Hyunsoo KimSeung Bum Park
Oct 27, 2018·Journal of the American Chemical Society·Victoria GeorgiAmaury Fernández-Montalván
Jul 3, 2021·Expert Opinion on Drug Discovery·Robert A Copeland

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Methods Mentioned

BETA
electrophoresis
blood collection

Software Mentioned

ImageQuant
MATLAB
WinNonlin
Mathematica

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