Journal ArticleDOI
PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor.
Hua Xu,Michael I. Jesson,Uthpala Seneviratne,Tsung H. Lin,M Nusrat Sharif,Liang Xue,Chuong Nguyen,Robert A. Everley,John I. Trujillo,Douglas S. Johnson,Gary R. Point,Atli Thorarensen,Iain Kilty,Jean-Baptiste Telliez +13 more
TLDR
Preclinical data demonstrate that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases.Abstract:
PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level of selectivity toward JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. Importantly, 10 other kinases in the kinome have a cysteine at the equivalent position of Cys-909 in JAK3. Five of those kinases belong to the TEC kinase family including BTK, BMX, ITK, RLK, and TEC and are also inhibited by PF-06651600. Preclinical data demonstrate that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases. On the basis of the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areata, and vitiligo, the dual activity of PF-06651600 toward JAK3 and the TEC kinase family may provide a beneficial inhibitory profile for therapeutic intervention.read more
Citations
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Journal ArticleDOI
Kinase inhibition in autoimmunity and inflammation
TL;DR: The activity of kinases that regulate production of inflammatory mediators and the recent advances in developing inhibitors to target such kinases are discussed.
Journal ArticleDOI
Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.
Stephen T. Wrobleski,Moslin Ryan M,Shuqun Lin,Yanlei Zhang,Steven H. Spergel,James Kempson,Tokarski John S,Joann Strnad,Adriana Zupa-Fernandez,Lihong Cheng,David J. Shuster,Kathleen M. Gillooly,Xiaoxia Yang,Elizabeth M. Heimrich,Kim W. McIntyre,Charu Chaudhry,Javed Khan,Max Ruzanov,Jeffrey Tredup,Dawn Mulligan,Dianlin Xie,Huadong Sun,Christine Huang,Celia D’Arienzo,Nelly Aranibar,Manoj Chiney,Anjaneya Chimalakonda,William J. Pitts,Louis J. Lombardo,Percy H. Carter,James R. Burke,David S. Weinstein +31 more
TL;DR: The late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2 are reported.
Journal ArticleDOI
Emerging Topical and Systemic JAK Inhibitors in Dermatology.
TL;DR: The immunological basis and current stage of development of JAKi in dermatology is discussed, which is emerging as a new class of drugs that can be used systemically as oral drugs or locally in topical formulations.
Journal ArticleDOI
An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells.
Ekaterina V. Vinogradova,Xiaoyu Zhang,David Remillard,Daniel C. Lazar,Radu M. Suciu,Yujia Wang,Giulia Bianco,Yu Yamashita,Yu Yamashita,Vincent M. Crowley,Michael A. Schafroth,Minoru Yokoyama,David B. Konrad,Kenneth M. Lum,Gabriel M. Simon,Esther K. Kemper,Michael R. Lazear,Sifei Yin,Megan M. Blewett,Melissa M. Dix,Nhan T. Nguyen,Maxim N. Shokhirev,Emily N. Chin,Luke L. Lairson,Bruno Melillo,Bruno Melillo,Stuart L. Schreiber,Stuart L. Schreiber,Stefano Forli,John R. Teijaro,Benjamin F. Cravatt +30 more
TL;DR: The findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.
Journal ArticleDOI
Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition
Martin E. Dowty,Tsung H. Lin,Michael I. Jesson,Martin Hegen,David Martin,Vaibhav Katkade,Sujatha Menon,Jean-Baptiste Telliez +7 more
TL;DR: Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these JAK inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition.
References
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Journal ArticleDOI
CD107a as a functional marker for the identification of natural killer cell activity
TL;DR: It is suggested that employing CD107a as a marker of NK cell functional activity may allow for the identification of a large fraction of activated NK cells that may degranulate in the absence of cytokine secretion.
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New insights into the regulation of T cells by |[gamma]|c family cytokines
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Paolo Macchi,Anna Villa,Silvia Giliani,Maria Grazia Sacco,Annalisa Frattini,Fulvio Porta,A. G. Ugazio,J A Johnston,Fabio Candotti,John J. O'Shea +9 more
TL;DR: Two unrelated T- B+SCID patients who have homozygous mutations in the gene for Jak-3 are investigated and abnormalities in the Jak/STAT signalling pathway can account for SCID in humans.
Journal ArticleDOI
Cytokine Signaling Modules in Inflammatory Responses
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T-Cell Signaling Regulated by the Tec Family Kinase, Itk
TL;DR: The complex role of Itk signaling in effector T-cell differentiation and the regulation of cytokine gene expression implicate Itk as an important modulator of T- cell signaling and function.
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