Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-RafV600E kinase |
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| Affiliation: | 1. Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States;2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080-4990, United States;1. Department of Medicinal Chemistry, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA;2. Department of Alzheimer’s Research, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA;3. Department of Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA;1. Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA;2. Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA;1. Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘Giulio Natta’, Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy;2. KemoTech, KemoTech s.r.l., Parco Scientifico della Sardegna, Edificio 3, Loc. Piscinamanna, 09010 Pula (CA), Italy;3. Dipartimento di Chimica e Farmacia dell’Università degli Studi di Sassari, Via F. Muroni 23/A, 07100 Sassari (SS), Italy;4. C.N.R.—Istituto di Farmacologia Traslazionale, Parco Scientifico della Sardegna, Edificio 5, Loc. Piscinamanna, 09010 Pula (CA), Italy;5. C.N.R.—Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘A. Quilico’, Via Mancinelli 7, 20131 Milano, Italy;6. Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK;1. Department of Medicinal and Pharmaceutical Chemistry, Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea;2. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea;1. Department of Biotechnology, School of Pharmaceutical Sciences, Siksha O Anushandan University (SOA), Bhubaneswar 751030, India;2. Institute of Materials Research and Engineering (IMRE), Agency for Science, Technology and Research (A*STAR), 3, Research Link, 117602, Singapore;3. Department of Chemical Engineering, Indian Institute of Technology Kanpur, Kanpur 208016, India |
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| Abstract: | Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery. |
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| Keywords: | B-Raf inhibitors Type IIB inhibitor Kinase drug discovery Melonoma |
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