6I8T

THE CATALYTIC FRAGMENT OF POLY(ADP-RIBOSE) POLYMERASE COMPLEXED WITH AN ISOINDOLINONE INHIBITOR

Summary for 6I8T

• Entry DOI: 10.2210/pdb6i8t/pdb
• Descriptor: Poly [ADP-ribose] polymerase 1, (1~{R})-2-(1-cyclohexylpiperidin-4-yl)-1-methyl-3-oxidanylidene-1~{H}-isoindole-4-carboxamide (3 entities in total)
• Functional Keywords: transferase, chicken parp1, inhibitor complex, adp-ribosylation, dna damage
• Biological source: Gallus gallus (Chicken)
• Total number of polymer chains: 1
• Total formula weight: 40983.10

Authors

Casale, E.,Papeo, G.,Montagnoli, A. (deposition date: 2018-11-21, release date: 2019-05-01, Last modification date: 2024-05-15)

Primary citation

Papeo, G.,Orsini, P.,Avanzi, N.R.,Borghi, D.,Casale, E.,Ciomei, M.,Cirla, A.,Desperati, V.,Donati, D.,Felder, E.R.,Galvani, A.,Guanci, M.,Isacchi, A.,Posteri, H.,Rainoldi, S.,Riccardi-Sirtori, F.,Scolaro, A.,Montagnoli, A.
Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515.
Acs Med.Chem.Lett., 10:534-538, 2019

PubMed 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.

PubMed: 30996792
DOI: 10.1021/acsmedchemlett.8b00569

Experimental method

X-RAY DIFFRACTION (2.1 Å)