Mark E. Schnute*, Gary M. Chinigo*, Kentaro Futatsugi, Masaya Yamaguchi, Scott W. Bagley, Mary Ellen Banker, Jeanne S. Chang, Ming Z. Chen, Won Young Choi, Matthew S. Corbett, Susan E. Drozda, David C. Ebner, Carmen Garcia-Irizarry, Robert Hicklin, Susan Hoy, Wenhua Jiao, Steven Kortum, Katherine L. Lee, David C. Limburg, Frank Lovering, Antonio Moreno, James J. Mousseau, Senliang Pan, Mihir D. Parikh, Jeffrey W. Pelker, Simeon Ramsey, Usa Reilly, Gwenaella Rescourio, Daniel C. Schmitt, Brittany Simpson, Grzegorz J. Skrzypek, Daniel J. Smaltz, Alexandria P. Taylor, Rubben Torella, John I. Trujillo, Felix F. Vajdos, James A. Wepy, Stephen W. Wright, David C. Blakemore, Fabien Vincent and Valerie M. Clerin,
{"title":"Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule","authors":"Mark E. Schnute*, Gary M. Chinigo*, Kentaro Futatsugi, Masaya Yamaguchi, Scott W. Bagley, Mary Ellen Banker, Jeanne S. Chang, Ming Z. Chen, Won Young Choi, Matthew S. Corbett, Susan E. Drozda, David C. Ebner, Carmen Garcia-Irizarry, Robert Hicklin, Susan Hoy, Wenhua Jiao, Steven Kortum, Katherine L. Lee, David C. Limburg, Frank Lovering, Antonio Moreno, James J. Mousseau, Senliang Pan, Mihir D. Parikh, Jeffrey W. Pelker, Simeon Ramsey, Usa Reilly, Gwenaella Rescourio, Daniel C. Schmitt, Brittany Simpson, Grzegorz J. Skrzypek, Daniel J. Smaltz, Alexandria P. Taylor, Rubben Torella, John I. Trujillo, Felix F. Vajdos, James A. Wepy, Stephen W. Wright, David C. Blakemore, Fabien Vincent and Valerie M. Clerin, ","doi":"10.1021/acsmedchemlett.5c00372","DOIUrl":null,"url":null,"abstract":"<p >Excess protein citrullination, a post-translational modification converting arginine to citrulline, has been associated with a range of autoimmune and neurological disorders, as well as cancers. Protein citrullination is mediated by the peptidylarginine deiminase enzyme family (PAD1–4), and inhibition of one or several PAD isozymes in combination may offer a therapeutic approach to targeting these diseases. Building upon the discovery of PAD–PF2, an allosteric inhibitor of PAD1–4, herein, we report on the optimization of potency and pharmacokinetic properties while minimizing hERG channel liabilities within this novel chemical series. Through structure-based ligand design, a structural water was successfully displaced, allowing expansion of the ligand binding site and access to a previously unexplored hydrophobic pocket resulting in a 10-fold improvement in potency. Compound <b>4f</b> demonstrated potent inhibition of PAD-mediated citrullination in human and rat neutrophils, reduced hERG channel liabilities, and good oral bioavailability in preclinical animal species.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1662–1669"},"PeriodicalIF":4.0000,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00372","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Excess protein citrullination, a post-translational modification converting arginine to citrulline, has been associated with a range of autoimmune and neurological disorders, as well as cancers. Protein citrullination is mediated by the peptidylarginine deiminase enzyme family (PAD1–4), and inhibition of one or several PAD isozymes in combination may offer a therapeutic approach to targeting these diseases. Building upon the discovery of PAD–PF2, an allosteric inhibitor of PAD1–4, herein, we report on the optimization of potency and pharmacokinetic properties while minimizing hERG channel liabilities within this novel chemical series. Through structure-based ligand design, a structural water was successfully displaced, allowing expansion of the ligand binding site and access to a previously unexplored hydrophobic pocket resulting in a 10-fold improvement in potency. Compound 4f demonstrated potent inhibition of PAD-mediated citrullination in human and rat neutrophils, reduced hERG channel liabilities, and good oral bioavailability in preclinical animal species.
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ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.
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