Structural highlights
Function[PARP1_CHICK] Poly[ADP-ribose] polymerase modifies various nuclear proteins by poly(ADP-ribosyl)ation. The modification is dependent on DNA and is involved in the regulation of various important cellular processes such as differentiation, proliferation, and tumor transformation and also in the regulation of the molecular events involved in the recovery of cell from DNA damage. Publication Abstract from PubMedPoly(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 (K d: 0.016 muM) and cellular (IC50: 0.027 muM) 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. Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515.,Papeo G, Orsini P, Avanzi NR, Borghi D, Casale E, Ciomei M, Cirla A, Desperati V, Donati D, Felder ER, Galvani A, Guanci M, Isacchi A, Posteri H, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Montagnoli A ACS Med Chem Lett. 2019 Mar 13;10(4):534-538. doi:, 10.1021/acsmedchemlett.8b00569. eCollection 2019 Apr 11. PMID:30996792[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
This page was last modified 08:48, 1 May 2019.