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N-phenyl ureidobenzenesulfonates,a novel class of promising human dihydroorotate dehydrogenase inhibitors |
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| Institution: | 1. Department of Chemistry, UCL, Christopher Ingold Building, 20, Gordon Street, London WC1H 0AJ, UK;2. Department of Structural and Molecular Biology, UCL, Gower Street, London WC1E 6BT, UK;3. Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK;1. Synthia LLC, Davis, CA 95616, United States;2. Department of Entomology and Nematology, One Shields Ave, University of California-Davis, Davis, CA 95616, United States;3. EicOsis Human Health, 140 B Street, Suite 5, Number 346, Davis, CA 95616, United States;1. Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, CNRS UMR8601, Paris, France;2. Department of Organic Chemistry, Yerevan State University, Yerevan, Armenia;3. Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy;4. Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France;5. Chimie Bio-inorganique des Dérivés Soufrés et Pharmacochimie (CBDSP), Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, CNRS UMR8601, Paris, France;6. Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, Université Lyon 1, ENS de Lyon, Lyon, France;7. Institut de Recherche en Infectiologie de Montpellier, CNRS UMR9004, Université de Montpellier, Montpellier, France;1. Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India;2. Institute of Science, Nirma University, Ahmedabad 382481, Gujarat, India;1. Cancer Biology, Oncology Division, Sanofi, Cambridge, MA 02138, USA;2. LGCR-LIT, Sanofi, Vitry-Sur-Seine 94400, France;3. Biochemistry, Bioanalytics, and Chemical Biology, Oncology Division, Sanofi, Cambridge, MA 02138, USA;4. Chemistry, Oncology Division, Sanofi, Cambridge, MA 02138, USA;5. LGCR-SDI, Oncology Division, Sanofi, Cambridge, MA 02138, USA;6. LGCR, Oncology Division, Sanofi, Cambridge, MA 02138, USA;7. TEM-BioInformatics, Oncology Division, Sanofi, Cambridge, MA 02138, USA;8. In Vivo Pharmacology, Oncology Division, Sanofi, Cambridge, MA 02138, USA;1. Department of Chemistry, Georgia State University, Atlanta, GA 30302, United States;2. Laboratório de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 14040-903, Brazil;3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, United States;4. Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Sao Paulo, 13083-970, Brazil |
| Abstract: | N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC50 = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest. |
| Keywords: | Anticancer agents Human dihydroorotate dehydrogenase inhibitors PUB-SOs SFOM-0046 DCIP"} {"#name":"keyword" "$":{"id":"k0035"} "$$":[{"#name":"text" "_":"2 6-dichlorophenolindophenol DHO"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "_":"dihydroorotate DSBs"} {"#name":"keyword" "$":{"id":"k0055"} "$$":[{"#name":"text" "_":"double-strand breaks DTP"} {"#name":"keyword" "$":{"id":"k0065"} "$$":[{"#name":"text" "_":"Developmental Therapeutics Program DUQ"} {"#name":"keyword" "$":{"id":"k0075"} "$$":[{"#name":"text" "_":"decylubiquinone FMN"} {"#name":"keyword" "$":{"id":"k0085"} "$$":[{"#name":"text" "_":"flavin mononucleotide hDHODH"} {"#name":"keyword" "$":{"id":"k0095"} "$$":[{"#name":"text" "_":"human dihydroorotate dehydrogenase PUB-SOs"} {"#name":"keyword" "$":{"id":"k0105"} "$$":[{"#name":"text" "$$":[{"#name":"italic" "_":"N"} {"#name":"__text__" "_":"-phenyl ureidobenzenesulfonates SFOM-0046"} {"#name":"keyword" "$":{"id":"k0115"} "$$":[{"#name":"text" "_":"2-ethylphenyl 4-(3-ethylureido)benzenesulfonate TCA"} {"#name":"keyword" "$":{"id":"k0125"} "$$":[{"#name":"text" "_":"trichloroacetic acid |
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