Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Apr 19

PMID 30996792

Citations 6

Authors

Gianluca Papeo

Paolo Orsini

Nilla R Avanzi

Daniela Borghi

Elena Casale

Marina Ciomei

Alessandra Cirla

Viviana Desperati

Daniele Donati

Eduard R Felder

Arturo Galvani

Marco Guanci

Antonella Isacchi

Helena Posteri

Sonia Rainoldi

Federico Riccardi-Sirtori

Alessandra Scolaro

Alessia Montagnoli

Affiliations

Soon will be listed here.

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.g., Lynparza, Rubraca, Zejula, and Talzenna) used for the treatment of ovarian, breast, and prostate tumors. Efforts in investigating an uncharted region of the previously identified isoindolinone carboxamide series delivered ()- (NMS-P515), a potent inhibitor of PARP-1 both in biochemical ( : 0.016 μM) and cellular (IC: 0.027 μM) assays. Cocrystal structure allowed explaining NMS-P515 stereospecific inhibition of the target. After having ruled out potential loss of enantiopurity in vitro and in vivo, NMS-P515 was synthesized in an asymmetric fashion. NMS-P515 ADME profile and its antitumor activity in a mouse xenograft cancer model render the compound eligible for further optimization.

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