title: Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.
abstract: The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Papeo
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Helena
authors.initials: H
authors.lastname: Posteri
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Borghi
authors.affiliation: Chemical Diversity Research Institute , Rabochaya St. 2 Khimki, Moscow Region 114401, Russia.
authors.forename: Alina A
authors.initials: AA
authors.lastname: Busel
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Caprera
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cirla
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Emiliana
authors.initials: E
authors.lastname: Corti
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: D'Anello
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Fasolini
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Forte
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.affiliation: Chemical Diversity Research Institute , Rabochaya St. 2 Khimki, Moscow Region 114401, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Khvat
authors.affiliation: Chemical Diversity Research Institute , Rabochaya St. 2 Khimki, Moscow Region 114401, Russia.
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Krasavin
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Rosita
authors.initials: R
authors.lastname: Lupi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Orsini
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Perego
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.affiliation: Accelera Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Pezzetta
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rainoldi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Riccardi-Sirtori
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scolaro
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sola
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Zuccotto
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Eduard R
authors.initials: ER
authors.lastname: Felder
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Montagnoli
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001682:Biological Availability; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004354:Drug Screening Assays, Antitumor; D005260:Female; D064593:Heterografts; D057166:High-Throughput Screening Assays; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D064726:Triple Negative Breast Neoplasms
chemical_list: D000970:Antineoplastic Agents; D054833:Isoindoles; C000603349:NMS-P118; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; D000077204:Temozolomide