Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Abstract

Purpose: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are b-nicotinamide adenine dinucleotide (NAD þ )-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD þ -competitive compounds with iniparib and its C-nitroso metabolite.Experimental Design: Two chemical series of NAD þ -competitive PARP inhibitors, iniparib and its C-nitroso metabolite, were analyzed in enzymatic and cellular assays. Viability assays were carried out in MDA-MB-436 (BRCA1-deficient) and DLD1À/À (BRCA2-deficient) cells together with BRCA-proficient MDA-MB-231 and DLD1 þ/þ cells. Capan-1 and B16F10 xenograft models were used to compare iniparib and veliparib in vivo. Mass spectrometry and the 3 H-labeling method were used to monitor the covalent modification of proteins.Results: All NAD þ -competitive inhibitors show robust activity in a PARP cellular assay, strongly potentiate the activity of temozolomide, and elicit robust cell killing in BRCA-deficient tumor cells in vitro and in vivo. Cell killing was associated with an induction of DNA damage. In contrast, neither iniparib nor its C-nitroso metabolite inhibited PARP enzymatic or cellular activity, potentiated temozolomide, or showed activity in a BRCA-deficient setting. We find that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins. Furthermore, both iniparib and its nitroso metabolite form protein adducts nonspecifically in tumor cells. Conclusions: Iniparib nonselectively modifies cysteine-containing proteins in tumor cells, and the primary mechanism of action for iniparib is likely not via inhibition of PARP activity. Clin Cancer Res; 18(2); 510-23. Ó2011 AACR.

Comparative antiproliferative effects of iniparib and olaparib on a panel of triple-negative and non-triple-negative breast cancer cell lines

“…Our findings suggest that response to both olaparib and iniparib is variable from cell line to cell line and independent of molecular subtype. Despite this variability, and in agreement with recent reports, 20,21 we found that olaparib was a more potent inhibitor of cell growth than iniparib in almost all the cell lines investigated. Our results are thus consistent with recent studies showing that iniparib was a weak inhibitor of PARP1.…”

Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET

“…However, these results could not be reproduced in a phase III trial, raising questions about the future of PARP inhibition as a therapeutic strategy. Remarkably, in striking analogy with tivantinib, subsequent studies showed that iniparib is not a PARP inhibitor but a cytotoxic agent that kills tumor cells by an unrelated molecular mechanism (37,38). In the iniparib as in the tivantinib case, more rigorous preclinical analysis would have addressed these drugs toward a more appropriate clinical testing, preventing failure, and misinterpretation of clinical trials (39).…”

The recent progress of neoadjuvant chemotherapy in triple negative breast cancer: A short review

“…Analogously, the interim analysis of the SOLTINeoPARP trial, a randomized phase II study that examined the efficacy of iniparib addition to weekly paclitaxel in the neoadjuvant setting of TNBC, failed to meet its primary endpoint that was pCR improvement [68] . Newer in vitro data though recognized that iniparib is not a selective PARP inhibitor [69,70] and its antineoplastic action could be attributed to the modification of cystein-containing proteins [69] , explaining its failure in the TNBC population. Other selective third generation PARP inhibitors, namely olaparib and veliparib, could be more effective and are investigated in clinical trials.…”