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Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold
Institution:1. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy;2. Scientia Advice di Roberto Artali, 20832 Desio (MB), Italy;3. Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milano, Italy;1. Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China;2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China;1. Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, via Celoria 2, 20133 Milano, Italy;2. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.,via Pontina Km 30, 400, I-00040 Pomezia (RM), Italy;3. Molecular Pharmacology Unit, Dept. Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, via Amadeo 42, I-20133 Milan, Italy;4. Scientia Advice, di Roberto Artali, 20832 Desio (MB), Italy;1. Chemogenomics Laboratory, Research Program in Biomedical Informatics (GRIB), IMIM Hospital del Mar Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain;2. Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, via del Liceo 1, 06123 Perugia, Italy;3. TES Pharma S.r.l., via Palmiro Togliatti 22bis, 06073 Corciano, Perugia, Italy;1. Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China;2. Department of Traditional Chinese Materia Medica and Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China;1. Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;2. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;3. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;4. Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Abstract:Poly(ADP-ribose)polymerase-I (PARP-1) enzyme is involved in maintaining DNA integrity and programmed cell death. A virtual screening of commercial libraries led to the identification of five novel scaffolds with inhibitory profile in the low nanomolar range. A hit-to-lead optimization led to the identification of a group of new potent PARP-1 inhibitors, acyl-piperazinylamides of 3-(4-oxo-3,4-dihydro-quinazolin-2-yl)-propionic acid. Molecular modeling studies highlighted the preponderant role of the propanoyl side chain.
Keywords:PARP-1 inhibitors  Anticancer  3-(4-Oxo-3  4-dihydro-quinazolin-2-yl)-propionamides  Molecular modeling  Virtual screening of commercial libraries  Hit-to-lead optimization
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