CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition

Autor: Yin Sy, Szychowski J, Natasha Chaudhary, Duffy Nm, Veloso A, Bowlan J, Stocco R, Papp R, Martino G, Singhania A, Rachel K. Szilard, Fourtounis J, Leclaire M, Liu B, Alejandro Álvarez-Quilón, de Rugy Tg, Nicolas O, Henrique Melo, Baruah Ps, Hunain Alam, Gary Marshall C, Young Jt, Dietrich E, Gallo D, Desjardins J, Bernier C, Fugère-Desjardins C, Tkáč J, Fournier S, Michael Zinda, Roulston A, Morris Sj, Fortin Ab, Daniel Durocher

Amplification of the gene encoding cyclin E (CCNE1) is an oncogenic driver in several malignancies and is associated with chemoresistance and poor prognosis. To uncover therapeutic targets forCCNE1-amplified tumors, we undertook genome-scale CRISPR/C

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https://doi.org/10.1101/2021.04.08.438361

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Identification of RP-6685 , an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.

Autor: Bubenik M; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Mader P; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada., Mochirian P; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Vallée F; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Clark J; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Truchon JF; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Perryman AL; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Pau V; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada., Kurinov I; Department of Chemistry and Chemical Biology, NE-CAT, Argonne, Cornell University, Illinois, New York 60439, United States., Zahn KE; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Leclaire ME; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Papp R; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Mathieu MC; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Hamel M; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Duffy NM; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Godbout C; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Casas-Selves M; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Falgueyret JP; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Baruah PS; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Nicolas O; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Stocco R; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Poirier H; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Martino G; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Fortin AB; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Roulston A; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Chefson A; Ventus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada., Dorich S; Ventus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada., St-Onge M; Ventus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada., Patel P; Ventus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada., Pellerin C; Ventus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada., Ciblat S; Ventus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.; Paraza Pharma Inc., 2525 Ave. Marie Curie, Montréal, Québec H4S 1Z9, Canada., Pinter T; Ventus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada., Barabé F; Paraza Pharma Inc., 2525 Ave. Marie Curie, Montréal, Québec H4S 1Z9, Canada., El Bakkouri M; Paraza Pharma Inc., 2525 Ave. Marie Curie, Montréal, Québec H4S 1Z9, Canada.; National Research Council of Canada, 6100 Royalmount Avenue, Montréal, Québec H4P 2R2, Canada., Parikh P; Piramal Pharma Ltd., Plot No. 18, Village Matoda, Taluka: Sanand, Ahmedabad, Gujarat 382213, India., Gervais C; National Research Council of Canada, 6100 Royalmount Avenue, Montréal, Québec H4P 2R2, Canada., Sfeir A; Molecular Biology Program, Sloan Kettering Institute, MSKCC, 430 E 67th Street, New York, New York 10065, United States., Mamane Y; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Morris SJ; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Black WC; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada., Sicheri F; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada., Gallant M; Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.

Publikováno v: Journal of medicinal chemistry [J Med Chem] 2022 Oct 13; Vol. 65 (19), pp. 13198-13215. Date of Electronic Publication: 2022 Sep 20.

CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition.

Autor: Gallo D; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Young JTF; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Fourtounis J; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Martino G; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Álvarez-Quilón A; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Bernier C; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Duffy NM; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Papp R; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Roulston A; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Stocco R; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Szychowski J; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Veloso A; Repare Therapeutics, Cambridge, MA, USA., Alam H; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Baruah PS; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Fortin AB; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Bowlan J; Repare Therapeutics, Cambridge, MA, USA., Chaudhary N; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Desjardins J; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Dietrich E; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Fournier S; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Fugère-Desjardins C; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Goullet de Rugy T; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Leclaire ME; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Liu B; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Bhaskaran V; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Mamane Y; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Melo H; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Nicolas O; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Singhania A; Repare Therapeutics, Cambridge, MA, USA., Szilard RK; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Tkáč J; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada., Yin SY; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Morris SJ; Repare Therapeutics, Saint-Laurent, Quebec, Canada., Zinda M; Repare Therapeutics, Cambridge, MA, USA., Marshall CG; Repare Therapeutics, Cambridge, MA, USA. gmarshall@reparerx.com., Durocher D; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. durocher@lunenfeld.ca.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. durocher@lunenfeld.ca.

Publikováno v: Nature [Nature] 2022 Apr; Vol. 604 (7907), pp. 749-756. Date of Electronic Publication: 2022 Apr 20.

A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency.

Autor: Daou S; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Talukdar M; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Tang J; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055 Shenzhen, China., Dong B; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195., Banerjee S; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195., Li Y; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Duffy NM; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Ogunjimi AA; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Gaughan C; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195., Jha BK; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195., Gish G; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Tavernier N; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Mao D; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Weiss SR; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Huang H; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055 Shenzhen, China; huang.hao@pku.edu.cn silverr@ccf.org sicheri@lunenfeld.ca., Silverman RH; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; huang.hao@pku.edu.cn silverr@ccf.org sicheri@lunenfeld.ca., Sicheri F; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; huang.hao@pku.edu.cn silverr@ccf.org sicheri@lunenfeld.ca.; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.

Publikováno v: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Oct 06; Vol. 117 (40), pp. 24802-24812. Date of Electronic Publication: 2020 Sep 21.