TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.

Introduction: HPK1, a member of the MAP4K family of protein serine/threonine kinases, is involved in regulating signal transduction cascades in cells of hematopoietic lineage. Recent data from HPK1 knockout animals and kinase-inactive knock-in animals underscores the role of HPK1 in negatively regulating lymphocyte activation. This negative-feedback role of HPK1 downstream of lymphocyte activation and function combined with its restricted expression in cells of hematopoietic origin make it an ideal drug target for enhancing anti-tumor immunity. Experimental Procedures: A structure-based drug design approach was used to identify potent and selective inhibitors of HPK1. Various biochemical and biophysical assays, as well as a primary in vitro T cell activation assay, were utilized for multiple rounds of structure-activity relationship (SAR) studies. In vivo target engagement and pharmacodynamic data were generated using an anti-CD3 mouse model. Results: In vitro, HPK1 small molecule inhibition resulted in enhanced IL-2 production in primary mouse T cells and in purified human T cells stimulated with a suboptimal dose of anti-CD3/anti-CD28. Increased selectivity of HPK1 inhibitors relative to T cell-specific kinases and within the MAP4K family was responsible for further enhancing the IL-2 response in activated T cells. In vivo, qd oral dosing of an HPK1 inhibitor completely abrogated phosphorylated SLP-76, induced by administration of anti-CD3. Furthermore, inflammatory cytokine production was enhanced in vivo upon HPK1 inhibition. Conclusion: Pharmacological blockade of HPK1 kinase activity represents a novel and powerful immunomodulatory approach for anti-tumor immunity. Citation Format: David Ciccone, Jennifer Rocnik, Vad Lazari, Ian Linney, Michael Briggs, Alan Collis, Christine Loh, Mark Ashwell, John Montana, Peter Tummino, Neelu Kaila. HPK1, hematopoietic progenitor kinase 1, is a promising therapeutic target for cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 942.

Modeling protein-ligand interactions has been a central goal of computational chemistry for many years. We here review recent progress toward this goal, and highlight the role free energy calculation methods and computational solvent analysis techniques are now having in drug discovery. We further describe recent use of these methodologies to advance two separate drug discovery programs targeting acetyl-CoA carboxylase and tyrosine kinase 2. These examples suggest that tight integration of sophisticated chemistry teams with state-of-the-art computational methods can dramatically improve the efficiency of small molecule drug discovery.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLeaving Group 18O Kinetic Isotope Effects on the Nonenzymic Hydrolyses of p-Nitrophenyl N-Acetyl-.alpha.-neuraminideMark Ashwell, Michael L. Sinnott, and Yulei ZhangCite this: J. Org. Chem. 1994, 59, 24, 7539–7540Publication Date (Print):December 1, 1994Publication History Published online1 May 2002Published inissue 1 December 1994https://pubs.acs.org/doi/10.1021/jo00103a064https://doi.org/10.1021/jo00103a064research-articleACS PublicationsRequest reuse permissionsArticle Views47Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

The hydrolyses of aryl alpha-glucosides of N-acetylneuraminic acid proceed by four processes: (i) the H3O+-catalyzed hydrolysis of the neutral molecule; (ii) the H3O+-catalyzed hydrolysis of the anion (the kinetically equivalent neutral hydrolysis of the neutral molecule being ruled out by a small solvent isotope effect and beta1g values close to zero); (iii) the spontaneous hydrolysis of the anion; (iv) a base-catalyzed process possibly involving nucleophilic attack of the ionized C9-OH at position 6. Secondary deuterium kinetic isotope effects (d2, pro-R, and d1, pro-S, at C3; d1 at C4) have been measured for the p-nitrophenyl glycoside undergoing processes i-iii by the isotopic quasi-racemate method, with the p-nitrophenyl L-N-acetylneuraminide being made by the Vasella route from L-glucose (Helv. Chim. Acta 1986, 69, 1172, 1191, and 1205). The effects support a flattened C-2(5) ring conformation for these processes and require some nucleophilic assistance by the C1 carboxylate group for processes ii and iii, despite the strained alpha-lactone ring that results. The implications for catalysis by sialidases and retaining glycosidases such as lysozyme are discussed.