Portal de Periódicos da CAPES

Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515

2019; American Chemical Society; Volume: 10; Issue: 4 Linguagem: Inglês

10.1021/acsmedchemlett.8b00569

1948-5875

Gianluca Papeo, Paolo Orsini, Nilla Avanzi, Daniela Borghi, Elena Casale, Marina Ciomei, Alessandra Cirla, Viviana Desperati, Daniele Donati, Eduard Felder, Arturo Galvani, Marco Guanci, Antonella Isacchi, Helena Posteri, Sonia Rainoldi, Federico Riccardi Sirtori, Alessandra Scolaro, Alessia Montagnoli,

Toxin Mechanisms and Immunotoxins

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 (S)-13 (NMS-P515), a potent inhibitor of PARP-1 both in biochemical (Kd: 0.016 μM) and cellular (IC50: 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.