Novel Tricyclic Poly(ADP-ribose) Polymerase-1 Inhibitors with Potent Anticancer Chemopotentiating Activity:  Design, Synthesis, and X-ray Cocrystal Structure

Koch, Stacie S. Canan; Thoresen, Lars; Tikhe, Jayashree; Maegley, Karen A.; Almassy, Robert J.; Li, Jianke; Yu, Xin; Zook, Scott E.; Kumpf, Robert A.; Zhang, Cathy; Boritzki, Theodore J.; Mansour, Rena N.; Zhang, Kanyin E.; Ekker, Anne; Calabrese, Chris R.; Curtin, Nicola J.; Kyle, Suzanne; Thomas, Huw D.; Wang, Lan-Zhen; Calvert, A. Hilary; Golding, Bernard T.; Griffin, Roger J.; Newell, David R.; Webber, S. E.; Hostomský, Zdeněk

doi:10.1021/jm020259n

Cited by 124 publications

(65 citation statements)

References 42 publications

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“…Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Invitrogen, Carlsbad, CA) supplemented with 10 % fetal bovine serum (FBS, Invitrogen) at 37 °C in a humidified CO 2 (5 %) incubator. The PARP inhibitors AG-014699 [15], AZD-2281 [16], and BSI-201 [20] were synthesized in the authors’ laboratory according to published procedures, and ABT-888 was purchased from ENZO Life Sciences (Plymouth Meeting, PA). Cisplatin was purchased from NovaPlus (Novation, Irving, TX).…”

Section: Methodsmentioning

confidence: 99%

“…a Structures and reported IC 50 values for PARP inhibition of AG-014699 [15], AZD-2281 [16], ABT-888 [17], and BSI-201 [18]. b MTT assays of the dose-dependent suppressive effects of AG-014699, AZD-2281, ABT-888, and BSI-201 on the viability of MDA-MB-468, MDA-MB-231, and Cal-51 cells in 5 % FBS-supplemented DMEM medium after 72 h of treatment.…”

Section: Figmentioning

confidence: 99%

“…Accordingly, we investigated the in vitro efficacies and mechanisms of anti-tumor action of AG-014699 (rucaparib) [15], AZD-2281 (olaparib) [16], ABT-888 (veliparib) [17], and BSI-201 (iniparib) [18], in TNBC cell lines harboring different genetic abnormalities; specifically, MDA-MB-468 (PTEN-null, p53 mutant, BRCA1 wt), MDA-MB-231 (PTEN wt, p53 mutant, BRCA1 wt), and Cal-51 (PI3KCA mutant, p53 wt, BRCA1 wt) [19]. Our results provide evidence supporting the involvement of non-PARP targeting mechanisms in anti-tumor efficacy of some PARP inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells

Chuang

Kapuriya

Kulp

et al. 2012

Breast Cancer Res Treat

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Despite recent advances in the clinical evaluation of various poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer (TNBC) patients, data defining potential anti-tumor mechanisms beyond PARP inhibition for these agents are lacking. To address this issue, we investigated the effects of four different PARP inhibitors (AG-014699, AZD-2281, ABT-888, and BSI-201) in three genetically distinct TNBC cell lines (MDA-MB-468, MDA-MB-231, and Cal-51). Assays of cell viability and colony formation and flow cytometric analysis were used to determine effects on cell growth and cell cycle progression. PARP-dependent and -independent signaling mechanisms of each PARP inhibitor were investigated by western blotting and shRNA approaches. Potential synergistic interactions between PARP inhibitors and cisplatin in suppressing TNBC cell viability were assessed. These PARP inhibitors exhibited differential anti-tumor activities, with the relative potencies of AG-014699 > AZD-2281 > ABT-888 > BSI-201. The higher potencies of AG-014699 and AZD-2281 were associated with their effects on G2/M arrest and DNA damage as manifested by γ-H2AX formation and, for AG-014699, its unique ability to suppress Stat3 phosphorylation. Abilities of individual PARP inhibitors to sensitize TNBC cells to cisplatin varied to a great extent in a cell context- and cell line-specific manner. Differential activation of signaling pathways suggests that the PARP inhibitors currently in clinical trials have different anti-tumor mechanisms beyond PARP inhibition and these PARP-independent mechanisms warrant further investigation.

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Section: Methodsmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells

Chuang

Kapuriya

Kulp

et al. 2012

Breast Cancer Res Treat

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“…Many commonly used anticancer treatments, such as radiotherapy, alkylating agents and camptothecins, damage DNA by causing SSBs, and prevention of SSB repair has been shown in preclinical studies to improve cell kill [19]. For this reason, PARP inhibitors were first developed as radio- or chemo-potentiating agents [20,21], the aim being to overcome cancer cell resistance to a DNA-damaging agent by preventing repair of the potentially lethal damage to the cancer cell caused by the treatment.…”

Section: Parp Activity and Inhibitionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase inhibition: a new direction for BRCAand triple-negative breast cancer?

Plummer

2011

Breast Cancer Res

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Inhibitors of poly(ADP-ribose) polymerase (PARP)-mediated DNA repair have shown promise in early clinical studies in the treatment of specific subgroups of breast cancer. Notably, phase II trials indicate that olaparib, an oral PARP inhibitor, has activity as a single agent in BRCA-related tumours, and that a combination of iniparib, an intravenous PARP inhibitor, and chemotherapy offers a survival advantage, compared with chemotherapy alone, in triple-negative breast cancer. Phase III data on the latter indication are expected in 2011. Intriguingly, iniparib does not increase toxicity when used as a chemo-potentiating agent, suggesting that it differs in its mechanism of action from other agents in this class. Overall, PARP inhibitors represent a potentially important new class of anti-cancer agents with two potential modes of action, as single agents causing synthetic lethality and as chemo-potentiating agents.

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“…benzimidazole-4-carboxamides and benzoxazole-4-carboxamides were designed and tested. Results proved that these compounds are considerably more active than 3-AB [24][25][26]. Additionally, the structurally modified derivative of these drugs, 2-(4-hydroxyphenyl)-1H-benzimidazole-4-carboxamide (NU1085), potentiates by about 3-fold the cytotoxicity of the monofunctional alkylating agent temozolomide and of the topoisomerase I inhibitor topotecan.…”

mentioning

confidence: 99%

PARP-1 inhibitors: a novel genetically specific agents for cancer therapy

Čipák

Jantová²

2010

neo

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401Over recent years the investigation of DNA repair pathways is a very attractive area of research. It is well known that cells have a number of overlapping pathways to protect the genome from DNA damage. Mutations that occur within these pathways represent an increased risk of malignant transformation and chemotherapy resistance [1]. Despite much research has focused on protecting cells from DNA damage and restoring their repair function, the concept of "synthetic lethality", that is, exploiting the vulnerability of tumor cells which have lost one DNA repair pathway by targeting a second repair pathway, is emerging and represents an interesting therapeutic approach [2].Breast cancer is the leading cause of cancer incidence and the second leading cause of cancer mortality in women. Germline mutations of the breast tumor suppressor genes BRCA1 and BRCA2 have been found to contribute to the most of the familial breast cancer cases [3,4]. Recent evidence suggests that tumor cells which have lost BRCA1 or BRCA2, components essential for DNA repair by homologous recombination (HR), are particularly sensitive to inhibitors of base excision repair pathway (BER) [5]. Poly(ADPribose) polymerase-1 (PARP-1) is an enzyme which plays an important role in the recognition and repair of single-strand DNA breaks (SSBs) via BER [6]. Thus, targeted therapy using PARP-1 inhibitors has become an important novel strategy for treating tumor cells with deficiency in BRCA1 or BRCA2.BRCA1 and BRCA2. BRCA1 and BRCA2 play important roles in the repair of DNA double-strand breaks (DSBs) by HR. This error-free pathway is used to repair DSBs that occur in late S/G 2 phase of the cell cycle as well as to repair DSBs resulting from unrepaired SSBs. BRCA1 signals the presence of DSBs, while BRCA2 has a direct role in repair itself by driving RAD51 to the DSB site. Following recognition of DSBs, BRCA1 is phosphorylated and leads to activation of DSB repair by HR [7][8][9]. In the absence of functional BRCA1 or BRCA2, cells become unable to undergo DNA repair by HR and activate the nonhomologous end joining and single-strand non-homologous end joining annealing pathways, which are error-prone and result in chromosomal instability or cell death (Figure 1). Poly(ADP-ribose) polymerase-1 (PARP-1).PARP-1 is the first characterized and the best known member of the PARP family, which currently comprises 18 members [10]. PARP-1 is an abundant nuclear enzyme implicated in cellular responses to DNA injury provoked by genotoxic stress, in transcriptional regulation, and in regulation of cell survival and cell death. It binds to nicked DNA as a homodimer and mediates protection of DNA. Upon binding to DNA breaks, it cleaves NAD + into nicotinamide and ADP-ribose moieties and polymerizes the latter through surface accessible glutamate residues onto nuclear acceptor proteins. When DNA is mildly dam- Received February 5,2010The nuclear poly(ADP-ribose) polymerase-1 (PARP-1) represents an important novel target in cancer therapy. The enzyme is essential for si...

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Novel Tricyclic Poly(ADP-ribose) Polymerase-1 Inhibitors with Potent Anticancer Chemopotentiating Activity: Design, Synthesis, and X-ray Cocrystal Structure

Cited by 124 publications

References 42 publications

Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells

Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells

Poly(ADP-ribose) polymerase inhibition: a new direction for BRCAand triple-negative breast cancer?

PARP-1 inhibitors: a novel genetically specific agents for cancer therapy

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