A fragment-based electrophile-first approach to target histidine with aryl-fluorosulfates: application to hMcl-1

A fragment-based electrophile-first approach to target histidine with aryl-fluorosulfates: application to hMcl-1 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A fragment-based electrophile-first approach to target histidine with aryl-fluorosulfates: application to hMcl-1 Maurizio Pellecchia, Giulia Alboreggia, Kendall Muzzarelli, Zahra Assar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6214862/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Journal of Medicinal Chemistry → Version 1 posted You are reading this latest preprint version Abstract Aryl-fluorosulfates are mild electrophiles that are very stable in biological media and in vivo and can efficiently react with the side chains of Lys, Tyr, or His residues, when properly juxtaposed by a high-affinity ligand. A more powerful approach to derive novel ligands would consist in starting from the covalent adduct and building the ligand off those initial interactions. While this strategy has been proven for Cys with molecular fragments containing Cys targeting electrophiles such as acrylamides, a corresponding strategy with fluorosulfates targeting His/Lys/Tyr residues has yet to be reported. We report here that a fragment library of aryl-fluorosulfates, when deployed with proper biophysical screening strategies, can identify initial covalent fragments. We report on novel strategies to enhance the success rate of such electrophile-based fragment screening for His/Lys/Tyr residues and to characterize the resulting hits. As an application we report on novel covalent fragment hits targeting hMcl-1 His 224. Biological sciences/Drug discovery/Drug screening Health sciences/Molecular medicine Histidine covalent aryl-fluorosulfates fragment-based drug design hMcl-1 electrophile-first drug discovery fragment-based drug design fragment-based ligand design Full Text Additional Declarations Yes there is potential Competing Interest. GA declares no conflict of interest. MP is a co-founder of Armida Labs, Inc. KM and ZA are employees of Cayman Chemical. Supplementary Files FBBDCOVALENTSI.pdf A fragment-based electrophile-first approach to target histidine with aryl-fluorosulfates: application to hMcl-1 nrreportingsummary.pdf nr-reporting-summary form FBBDCOVALENTSIREVISED.pdf SUPPLEMENTARY INFORMATION FOR: A fragment-based electrophile-first approach to target histidine with aryl-fluorosulfates: application to hMcl-1 Cite Share Download PDF Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Journal of Medicinal Chemistry → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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