دورية أكاديمية
أعرض في EDS

A Versatile Isocyanate-Mediated Strategy for Appending Chemical Tags onto Drug-Like Small Molecules.

التفاصيل البيبلوغرافية
العنوان: A Versatile Isocyanate-Mediated Strategy for Appending Chemical Tags onto Drug-Like Small Molecules.
المؤلفون: Henry CC; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States., Kruell JA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States., Wilson RM; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States., Chang CF; Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States., Woo CM; Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States., Koehler AN; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States.
المصدر: Bioconjugate chemistry [Bioconjug Chem] 2023 Dec 20; Vol. 34 (12), pp. 2181-2186. Date of Electronic Publication: 2023 Dec 05.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9010319 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4812 (Electronic) Linking ISSN: 10431802 NLM ISO Abbreviation: Bioconjug Chem Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Chemical Society, c1990-
مواضيع طبية MeSH: Isocyanates* , Tacrolimus Binding Protein 1A*, Drug Discovery ; Sulfhydryl Compounds ; Photoaffinity Labels/chemistry
مستخلص: Target identification studies are a major hurdle in probe and drug discovery pipelines due to the need to chemically modify small molecules of interest, which can be time intensive and have low throughput. Here, we describe a versatile and scalable method for attaching chemical moieties to a small molecule, isocyanate-mediated chemical tagging (IMCT). By preparation of a template resin with an isocyanate capture group and a cleavable linker, nucleophilic groups on small molecules can be modified with an enforced one-to-one stoichiometry. We demonstrate a small molecule substrate scope that includes primary and secondary amines, thiols, phenols, benzyl alcohols, and primary alcohols. Cheminformatic analyses predict that IMCT is reactive with more than 25% of lead-like compounds in publicly available databases. To demonstrate that the method can produce biologically active molecules, we generated FKBP12 photoaffinity labeling (PAL) compounds with a wide range of affinities and showed that purified and crude cleavage products can bind to and label FKBP12. This method could be used to rapidly modify small molecules for many applications, including the synthesis of PAL probes, fluorescence polarization probes, pull-down probes, and degraders.
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معلومات مُعتمدة: P30 CA014051 United States CA NCI NIH HHS; U54 CA143874 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Isocyanates)
EC 5.2.1.- (Tacrolimus Binding Protein 1A)
0 (Sulfhydryl Compounds)
0 (Photoaffinity Labels)
تواريخ الأحداث: Date Created: 20231205 Date Completed: 20231221 Latest Revision: 20240228
رمز التحديث: 20240228
مُعرف محوري في PubMed: PMC10739574
DOI: 10.1021/acs.bioconjchem.3c00352
PMID: 38052453
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4812
DOI:10.1021/acs.bioconjchem.3c00352