INTRODUCTION:

TNBC is now one of the most active areas of research in oncology. A patient suffering from this subset of breast cancer undergoes an extremely testing and thwarting situation. TNBC, a heterogenous breast cancer subdivision, shows only a limited overlying with the so-called basal breast cancer. Hence it can be said that “triple negative” and “basal-like” are not fully interchangeable. It has to be kept in mind that not all TNBC are of basal-like subtype and not all basal-like breast cancer is triple negative. By definition, triple negative implies to the immune histo-chemical classification of breast tumours lacking ER, PR and HER2 expression although the basal-like subdivision is explained via gene expression microarray analysis^[5,6].

Currently, there are six sub-types of TNBC which includes basal-like 1(BL-1), basal-like 2(BL-2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR)-positive^[7].

Gene Expression profiling has proved that relatively 80% of all TNBC tumours are basal-like^[8]. Basal-like TNBC can be indicated by noticeable risk factors: aggressive and early The Gene Expression profiling has proved that relatively 80% of all TNBC tumours are basal-like^[6]. Basal-like TNBC can be indicated by noticeable risk factors: aggressive and early patterns of metastases, exclusive molecular characteristics, association with BRCA1 mutations, corresponding lack of targeted therapeutics and poor prognosis and patient survival rate^[9-16]. The BL-1 sub-type is outlined by an enriched cell cycle and DNA damage response gene expression^[7]. Enhancement in proliferation genes and expanded Ki-67 expression in basal-like TNBC can be the reason why this type responded well to antimitotic agents such as taxanes and DNA damaging agents like Cisplatin^[17,18].

Clinical attributes of TN tumors includes markedly elevated mitotic count, axillary node involvement, tumour necrosis, pushing margin of invasion and stromal lymphocytic response and high nuclear-cystoplasmic ratio^[19,20]. These tumours are histologically ductal invasive carcinomas characterized by poor differentiation, high proliferative capacity and overall large tumour size, but metaplastic and medullary histologies are also observed^[21]. It was observed that these tumours frequently disseminate to the lungs and the brain tissue which is contradictory to what is observed in other subtypes of breast cancer where metastasis occurs in bone and soft tissue^[22-24]. Furthermore, the entrenched correlation between tumour size and positive lymph nodes which has been detected in other breast cancer subdivisions is not pertinent to TN tumours^[25]. TNBC is more rampant in women of African-American and Hispanic origin and in younger women (age less than 40)^[9,23]. The first five year survival rate in TNBC is predicted at 70% which is lower than the 80% observed in other subdivisions.

POLY (ADP-RIBOSE) POLYMERASES 1 (PARP-1):

Poly (ADP-Ribose) Polymerases constitute a clan of enzymes which are liable for the catalyzed transfer of ADP-ribose moieties onto specific acceptor proteins and transcription factors, utilizing nicotine adenine nucleotide (NAD+) as the substrate^[26,27]. They consist of linear and/or branched repeats of ADB-ribose, which can be long up to 200 units.

PARP1 which is the most abundant, ubiquitously expressed nuclear protein is involved in the mediation of DNA damage response (at this stage, its enzymatic activity was observed to increase about 500-fold) and is the best defined isoform of the PARP family^[28]. It is accountable for the 85-90% of the total poly (ADP-ribosylation) activity and is localized within the cell nucleus^[29]. It binds with the DNA via two zinc finger motifs and relocates chains of ADP-ribose moieties from NAD⁺ to the chromatin-associated acceptor proteins. The covalent modifications catalyzed by the PARP1 is responsible for the regulation of the activity of proteins involved in the regeneration of DNA damages and the preservation of genome stability, gene transcription, proliferation, and differentiation of cells, and other processes^[30,31]. PARP1 plays an active role in in several biological mechanisms counting hypoxic response, transcriptional regulation, maintenance of chromosome stability, DNA repair and apoptosis^[32,33]. It principally operates as a DNA repair factor, chiefly in base excision repair. Other therapeutic areas save for cancer, where PARP1 is involved are stroke, inflammation, cardiac ischemia and diabetes^[34-37]. Accelerated binding of the PARP1 with the DNA strand breaks is essential for the resealing of the DNA single strand breaks during base excision repair and for the overhaul of DNA double strand breaks and topoisomerase I cleavage complexes. The gravity of PARP1 in cancer was further reinforced by two recent seminal preclinical studies^[38,39] where it was unveiled that the cell lines deficient in BRCA1 and BRCA2 (faulty in homologous recombination repair) were 1000 times more susceptible to PARP inhibition compared to the wild-type or heterozygous mutant cells. This discovery accentuated that PARP1 is the synthetic lethal ally of BRCA1 and BRCA2 and inhibition of PARP1 can prompt vastly scrupulous killing of BRCA1/2-deficient tumour cells^[36]. PARP1 has an indispensable role in the repair of single strand breaks by the base excision repair pathway.

The PARP1 enzyme (Figure 1) is a 113kDa protein accompanying three primary structural domains, a DNA binding domain with two zinc fingers, a 55kDa catalytic domain which employs NAD+ as the substrate to shape polymers of ADP-ribose on histones and the additional acceptor nuclear protein encompass the automodification domain of PARP1 itself^[40-42]. NAD+ binding site of PARP-1 contains two distinctive binding zones, specifically, a nicotinamide–ribose binding site (NI site) and an adenine–ribose binding site (AD site)^[43].

Figure 1: The PARP1 enzyme accompanying three primary structural domains

DNA damage generated by peroxidation^[44], irradiation^[45], and DNA damaging chemicals like chemotherapeutic agents^[46] prompt the catalytic activity of PARP-1. Subsequently to DNA damage, the 42kDa DNA binding domain with two zinc fingers binds with the damaged DNA and triggers polymerization of ADP-ribose culminating in the unfolding of DNA from histones and disclosing the damaged DNA for repair^[41]. The 2’-OH of the substrate NAD⁺ binds to an intermediate oxonium ion which is generated by the detachment of nicotinamide from the ribose ring. A hydrogen bonding network is formed between critical amino acid residues which includes Ser904 and Gly863 with the nicotinamide moiety^[46]. Further, Tyr904 forms a planar surface which develops a pi-pi interaction with the nicotinamide moiety and maintains the oxonium ion. Simultaneously, Glu988 expedites the proton transfer from the 2’-OH group before the glycosidic bond is established^[47]. The synthesis of branched polymers from the 2’-OH of the nicotinamide ribose is also mobilized by PARP1.

MECHANISMS OF PARP1 INHIBITORS FOR ANTICANCER ACTIVITY:

PARP1 inhibition (Figure 2) when considered as a target for oncology, acts as a chemopotentiator considering the fact that most of the anticancer therapeutics focus on DNA damage as a tool to eradicate the expeditiously splitting cancer cells. DNA repair for abundant cancerous cell types is carried out by the PARP1 mediated repair pathway^[48]. Therefore, inhibition of PARP1 along with DNA damaging chemotherapeutics or radiation is a very competent tool to jeopardize the cancer cell DNA repair mechanism, ensuing genomic dysfunction and cell death.

Figure 2: Mechanisms of PARP1 Inhibitors for Anticancer Activity

Breast Cancer linked genes BRCA and BRCA2 have been distinguished hitherto as tumor suppressor genes that play a indispensable part in the repair of double strand breaks (DSB) in DNA via a process called homologous recombination^[49]. Albeit PARP1 inhibition will contribute to an escalation in single strand breaks (SSB), the prevalence of these SSBs will ultimately lead to DSBs through replication fork collapse^[50]. The hike of DSBs in the existence of HR lacking cell types causes chromosomal aberrations and vulnerability of the genome resulting in cell death. This incident is referred to as synthetic lethality^[51], specifically since the loss of one gene function will result in cell susceptibility (i.e., the loss of PARP1 or BRCA1/2) but the loss of both is fatal (i.e., BRCA1/2 deficient cells and PARP1 inhibitor) ^[52].

Another mechanism of PARP1 inhibition exerting anticancer property, involves the interactions between DNA, PARP1 and its inhibitors which results in inhibition of PARP1 catalytic activity and ambush of the DNA-PARP1 complexes^[53]. Noncovalent DNA-PARP complexes occur normally in intact cells. When PARP1 inhibitors bind to the NAD+ binding pocket of the PARP1, an allosteric conformational change is promoted and reversible association of PARP1/2 with DNA is preserved. This mechanism is termed as the trapping of DNA-PARP1/2 complexes^[52,54-56]. Methodical observations^[56] reveals that the DNA-PARP trapping ability of PARP1 inhibitors has a much greater correlation with their cytotoxicity than their capability to suppress PARP1 catalytic activity. Levels of DSBs are more significantly correlated with cell death than are levels of trapping. Cell killing effect of this entrapment, are generally through the transformation of unrepaired SSBs into lethal DSBs.

Categories Of Parp1 Inhibitors:

PARP1 inhibitors target the NAD⁺ binding site by occupying the nicotinamide pocket. The first discovered inhibitors 3-amino/nitrobenzamides (Figure 3) which is structurally analogous to the PARylation by-product nicotinamide^[57]. These compounds showed low-to-moderate activity against PARP1 and non-optimal PK properties. Second generation of PARP1 inhibitors were more effective and target specific and were developed based on quinazoline analogues (specifically, 1,5-dihydroisoquinoline)^[58]. In fact, development of various newer drug groups was based on these molecules. Majority of the rest PARP1 inhibitors are bicyclic and tricyclic compounds where the pivotal carboxamido moiety is buried inside a ring system to form a lactam. Meanwhile an ancillary appendage with a shorter or longer linking chain is usually adhered to the polycyclic core as a solvent accessory region, which is generally required to connect the NI binding and AD binding units^[59-61]. This chain is also paramount for the potency and the physicochemical properties of the inhibitors.

Figure 3: The first discovered inhibitors 3-amino/nitrobenzamides

Nowadays, generally two types of PARP1 inhibitors are observed, consistently endowed with two distinguishing nicotinamide-mimic motifs (1) a rotationally constrained primary amide, in particular clinical candidates like Veliparib (Abbott)^[62] and Niraparib (Merck)^[63] or (2) an amide embedded in a ring as in Rucaparib (Pfizer/ Clovis)^[64], Olaparib (Astra Zeneca)^[65] now marketed as Lynparza and Talaxoparib (BioMarin)^[66]. The figure 4 shows above mentioned PARB inhibitors. From the PARP family of enzymes, none of the above mentioned inhibitors selectively inhibits PARP1. For example, all the clinical candidates and extensive majority of stated inhibitors also interact with PARP 2 with similar potencies. PARP-2 (aka ARTD-228) which is a 62 kDa nuclear protein and similar to PARP-1, is involved in DNA single-strand break repair. Yet, its input is nominal (5 −10%) to the total DNA damage induced PARP activity^[67].

Figure 4: PARB inhibitors

Olaparib, a robust oral PARP inhibitor is fatal to cells accommodating BRCA1 or BRCA2 mutations. During Phase I trial, the pharmcokinetic and pharmacodynamic parameters of the olaparib capsule formulation was established by Fong et al. where it was determined that pharmacokinetic characteristics at twice-daily dosing was rapid absorption and elimination^[55]. The peak plasma concentration of Olaparib was attained within 1-3 h after its intake, following a biphasic slump in plasma concentrations with a terminal elimination half-life of 5-7 h. Olaparib is mainly metabolized via dehydrogenation and oxidation, with a number of components which are further metabolized by glucuronide or sulphate conjugation. Cytochrome P450 (CYP) 3A4 is the principal metabolizing enzyme of olaparib, hence coadministration of olaparib with strong or moderate CYP3A4 inhibitors or inducers is generally avoided. Ang et al carried out a mass balance study of olaparib and established that excretion of the drug occurs primarily via faeces (42%) and urine (44%).

Interactions of PARP1 with its inhibitor:

H-bonding networks formed between the carboxamido component and Ser904 and Gly863 of PARP1, and the π–π stacking between the aryl ring and Tyr907 were the interactions observed in the 3-amino/nitrobenzamides, the first inhibitors^[59]. All of the known PARP1 inhibitors showed interactions via molecular modelling studies, with the NI site through three vital hydrogen bonds formed between the lactam or the carboxamide group of the small molecules and residues Ser904 and Gly863 of the catalytic site^[68,69]. (Figure 5)

Figure 5: Interactions of PARP1 with its Inhibitor

Furthermore, a pi-pi stacking interaction between the aromatic scaffold of PARP1 inhibitors and Tyr 896 and Tyr 907 of the NI site was customarily detected as additional fundamental feature. The AD site is quite large when compared with the nearly cramped NI site and can be used to search for an extensive range of novel inhibitors with the enhanced potency and pharmacokinetic properties^[70].

Cyclic inhibitors which are conformationally constrained establish an anti-disposition of the amide bond. Improved PARP inhibitor’s affinity to the binding site can be observed by locking the carboxamide moiety which is usually free to rotate. This locking process can be done by either introducing heteroatoms or groups on the aromatic ring which are able to provide an intramolecular hydrogen bond with the amide NH, or encompassing the amide group into a two (or more) ring heterocycle^[59].

Analysing these findings, a pharmacophore query was created by Giannini et al. where presence of three structural features were enforced (a) an aromatic ring, (b) a carboxamide moiety with at least one NH group into the desired anti-conformation, and (c) a side chain extending into the deep cavity placed in the auto-modification domain of PARP1.

Recent study on novel scaffold for PARP1 inhibitior:

Fu et al discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors. Lead Optimization resulted in the identification of compound (2-(11-(3-(dimethylamino)propylidene)-6,11-dihydrodibenzo[b,e] oxepin)-2yl)acetohydrazide), which showed a novel chemical scaffold and exclusive binding interactions with PARP1 protein. This particular compound exhibited excellent potency (inhibiting PARP1 enzyme activity with IC50 = 0.079μM) as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells (BRCA1 mutation). Further, the compound also inhibited cell migration that is closely associated to cancer metastasis and presented exceptional anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicity. Structure based Pharmacophore detection led to four common features on comparison, comprising A1 (hydrogen bond acceptor), D1 (hydrogen bond donor), AR1 (ring aromatic) and H1(hydrophobic). Extensive Structural Activity Relationship (Figure 6) was operated after recognising the most potent compound. The scaffold was classified into three rings. The activity of seven membered rings in Part A was found to be remarkable on comparison with the six membered ring, and when the substituent X is O, the activity was better. In Part B, higher activity was observed when R2 was substituted for different amide groups. Carbon chain requires a certain length in Part C and the best activity was noticed when R1 was substituted with tertiary amine groups.

Figure 6: Structural Activity Relationship for Novel Scaffold for PARP1 Inhibition

Clinical relevance of PARP1 inhibitors:

During clinical evaluation of PARP1 inhibitors, the compounds were tested against breast, ovarian or pancreatic cancer accommodating BRCA defects. Along with this investigation, these inhibitors along with the traditional chemotherapeutic agents were also studied against other solid tumors, including non small cell lung cancer and glioblastoma. The best response of Olaparib was shown against BRCA-mutated breast cancer. Olaparib was used in combination with DNA damaged agents, microtubule inhibitors, angiogenesis inhibitors and kinase inhibitors during the clinical trials. From six Phase I studies, this compound was acknowledged to improve the therapeutic response of patients with various cancers to cisplatin, carboplatin and pegylated liposomal doxorubicin, a topoisomerase II inhibitor, along with increased toxicities^[71-73]. Combination of Olaparib and Cediranib, a vascular endothelial growth factor receptor (VEGFR) inhibitor showed progress in the therapeutic efficacy in patients with ovarian cancer regardless of BRCA stature^[74,75]. Gefitinib, an epidermal growth factor receptor and the panphosphatidylinositol 3-kinase (PI3K) inhibitor were found to offer supplementary clinical assistance with use of Olaparib^[76,77].

CONCLUSION:

PARP1 plays important roles in both DNA repair and transcription, and the interplay of these processes in relation to cellular function and diseases states have not been well defined. As PARP1 binding motifs may be readily found in promoter elements of DNA repair genes, the expanding role of PARP1 in DNA repair need not be independent of transcription. The discovery of ADP-ribose binding modules that bind to various forms mono- and poly- ADP-ribose has provided important insights into how ADP-ribosylation regulates different cellular pathways. Among the four distinct PAR-binding modules discovered so far, it is the macrodomain alone that, in addition to possessing binding activity, in some instances also supports a catalytic activity toward ADP-ribose derivates. However, the development of PARP inhibitors as chemopotentiating agents has been limited by an increase in observed toxicities, mainly myelosuppression, necessitating dose reductions of the cytotoxic chemotherapeutic agent and the PARP inhibitor. Hence it presents an opportunity to rationally develop combinations of PARP inhibitors with new classes of DNA repair inhibitors that are on the horizon, and classical cytotoxic agents. In this reviwe, triple negative breast cancer, PARP1 and inhibitors, its role in TNBC, mechanism, categories, interactions, recent study on novel scaffold and clinical significance of PARP1 inhibitors were deliberated and reviewed.

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Received on 25.01.2019 Modified on 20.02.2019

Research J. Pharm. and Tech. 2019; 12(6):3098-3104.

DOI: 10.5958/0974-360X.2019.00524.9