Abstract 3259: Novel isoquinolinone derivatives with dual PARP-1/PARP-3 inhibitory activity are highly active against pTEN mutated colorectal cancer and glioblastoma models..

Abstract

Abstract Inhibitors of the poly(ADP-ribose) polymerases (PARPs) family of proteins are currently in clinical trials as potential anticancer agents. PARP-1 is a key nuclear enzyme activated by DNA strand breaks and its activation contributes to the recruitment of DNA repair and checkpoint proteins to the sites of damage. PARP-2 shows overlapping functions with PARP-1, as demonstrated by the embryonic lethality phenotype observed in double knockout mice, compared with the viability observed for single knockout of either gene. Genetic disruption in mice of PARP-2, but not of PARP-1, has been reported to affect different processes including spermatogenesis, adipogenesis, and thymocyte survival. It has been demonstrated that BRCA1 and BRCA2-deficient cell lines are sensitive towards PARP inhibition through prevention of DNA damage repair. However, recent studies have highlighted new potential genetic backgrounds in which PARP inhibition may have a therapeutic rationale. Accordingly, it has been reported that tumor cell lines bearing PTEN mutations, or with defects in mismatch repair genes are sensitive to PARP inhibitors. Here we describe the in vitro and in vivo characterization of small molecule inhibitors belonging to the isoquinolinone chemical class, with dual PARP-1 and PARP-3 inhibitory activity and which are selective versus PARP-2. Representative compounds of the class, such as NMS-P914, whose co-crystal structure with the human PARP-1 catalytic domain will be shown, and NMS-P648, are endowed with nanomolar potency against PARP-1 and PARP-3, are >100 selective versus PARP-2, possess almost complete oral bioavailability in the mouse and excellent in vitro ADMET properties across species. In cells, NMS-P914 and NMS-P648 inhibit DNA damage-induced PARP-1 activity with an IC50 of 1 nM and display single agent cytotoxicity in BRCA deficient breast tumor cell lines (IC50 < 100 nM). Interestingly, NMS-P914 and other members of the class also display similar potency against colorectal cancer and glioblastoma cell lines bearing defects in pTEN and in mismatch repair genes, and are active against glioblastoma cell lines resistant to temozolomide, irinotecan and to known PARP inhibitors such as olaparib and veliparib. In combination studies, NMS-P914 was found to be synergistic with temozolomide, both in temozolomide sensitive and resistant glioblastoma contexts. Furthermore, combination of NMS-P914 with temozolomide gives prolonged tumor regression without increasing temozolomide toxicity in vivo, showing better tolerability compared to temozolomide combination with olaparib. Citation Format: Alessia Montagnoli, Sonia Rainoldi, Stefania Mazzoleni, Antonella Ciavolella, Rosita Lupi, Elena Casale, Marina Ciomei, Enrico Pesenti, Daniele Donati, Arturo Galvani, Gianluca Papeo. Novel isoquinolinone derivatives with dual PARP-1/PARP-3 inhibitory activity are highly active against pTEN mutated colorectal cancer and glioblastoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3259. doi:10.1158/1538-7445.AM2013-3259