Vinylpyridine as a Tunable Covalent Warhead Targeting C797 in EGFR.
| Autor: | Pemberton N; Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 50, Sweden., Compagne N; Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 50, Sweden., Argyrou A; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom., Evertsson E; Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 50, Sweden., Gunnarsson A; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 50, Sweden., Kettle JG; Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom., Orme JP; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom., Ward RA; Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom. |
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| Jazyk: | angličtina |
| Zdroj: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Apr 05; Vol. 15 (5), pp. 583-589. Date of Electronic Publication: 2024 Apr 05 (Print Publication: 2024). |
| DOI: | 10.1021/acsmedchemlett.3c00425 |
| Abstrakt: | To further facilitate the discovery of cysteine reactive covalent inhibitors, there is a need to develop new reactive groups beyond the traditional acrylamide-type warheads. Herein we describe the design and synthesis of covalent EGFR inhibitors that use vinylpyridine as the reactive group. Structure-based design identified the quinazoline-containing vinylpyridine 6 as a starting point. Further modifications focused on reducing reactivity resulted in substituted vinyl compound 12 , which shows high EGFR potency and good kinase selectivity, as well as significantly reduced reactivity compared to the starting compound 6 , confirming that vinylpyridines can be applied as an alternative cysteine reactive warhead with tunable reactivity. Competing Interests: The authors declare no competing financial interest. (© 2024 American Chemical Society.) |
| Databáze: | MEDLINE |
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