Potent poly(ADP-ribose) Polymerase Research Articles

Design, synthesis, biological evaluation of novel piperidine-based derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors

Poly(ADP-ribose) polymerase-1 (PARP-1) is a crucial member of DNA repair enzymes responsible for repairing DNA single-strand breaks. Developing PARP inhibitors based on synthetic lethality strategies is an effective approach for treating breast cancer and other diseases. In this study, a series of novel piperidine-based benzamide derivatives were designed and synthesized using structure-based drug design principles. The anticancer activities of these compounds were evaluated against five human cancer cell lines (MDA-MB-436, CAPAN-1, SW-620, HepG2, SKOV3, and PC3) and the preliminary structure–activity relationships were delineated. Among the compounds, 6a and 15d demonstrated potent antiproliferative effects against MDA-MB-436 cells with IC50 values of 8.56 ± 1.07 μM and 6.99 ± 2.62 μM, respectively. Furthermore, both compounds exhibited excellent inhibitory activity against PARP-1, with IC50 values of 8.33 nM and 12.02 nM, respectively. Mechanistic investigations revealed that 6a and 15d effectively inhibited colony formation and cell migration of HCT116 cells. Moreover, they induced apoptosis by upregulating the expression of Bax and cleaved Caspase-3, while downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. Based on its impressive pharmacodynamic data in vitro, we conducted a study to evaluate the efficacy of 15d in a xenograft tumor model in mice when used in combination with cytotoxic agents. Collectively, these findings suggest that 15d could be promising drug candidates worthy of further investigation.

Abstract LB260: Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly polymerase inhibitor

Abstract Aims: The overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment. Methods: The cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration. Results: Talazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models. Conclusions: The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment. Citation Format: Shuo Fang, Xiaona Fang. Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly polymerase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB260.

Melatonin derivative 6a as a PARP-1 inhibitor for the treatment of Parkinson's disease.

Both continuous oxidative stress and poly (ADP-ribose) polymerase 1 (PARP-1) activation occur in neurodegenerative diseases such as Parkinson's disease. PARP-1 inhibition can reverse mitochondrial damage and has a neuroprotective effect. In a previous study, we synthesized melatonin derivative 6a (MD6a) and reported that it has excellent antioxidant activity and significantly reduces α-synuclein aggregation in Caenorhabditis elegans; however, the underlying mechanism is largely unknown. In the present study, we revealed that MD6a is a potential PARP-1 inhibitor, leading to mammalian targe of rapamycin/heat shock factor 1 signaling downregulation and reducing heat shock protein 4 and 6 expression, thus helping to maintain protein homeostasis and improve mitochondrial function. Together, these findings suggest that MD6a might be a viable candidate for the prevention and treatment of Parkinson's disease.

Type III secretion system effector YfiD inhibits the activation of host poly(ADP-ribose) polymerase-1 to promote bacterial infection

Modulation of cell death is a powerful strategy employed by pathogenic bacteria to evade host immune clearance and occupy profitable replication niches during infection. Intracellular pathogens employ the type III secretion system (T3SS) to deliver effectors, which interfere with regulated cell death pathways to evade immune defenses. Here, we reveal that poly(ADP-ribose) polymerase-1 (PARP1)-dependent cell death restrains Edwardsiella piscicida’s proliferation in mouse monocyte macrophages J774A.1, of which PARP1 activation results in the accumulation of poly(ADP-ribose) (PAR) and enhanced inflammatory response. Moreover, E. piscicida, an important intracellular pathogen, leverages a T3SS effector YfiD to impair PARP1’s activity and inhibit PAR accumulation. Once translocated into the host nucleus, YfiD binds to the ADP-ribosyl transferase (ART) domain of PARP1 to suppress its PARylation ability as the pharmacological inhibitor of PARP1 behaves. Furthermore, the interaction between YfiD and ART mainly relies on the complete unfolding of the helical domain, which releases the inhibitory effect on ART. In addition, YfiD impairs the inflammatory response and cell death in macrophages and promotes in vivo colonization and virulence of E. piscicida. Collectively, our results establish the functional mechanism of YfiD as a potential PARP1 inhibitor and provide more insights into host defense against bacterial infection.

Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly (ADP-Ribose) polymerase inhibitor

AimsThe overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment. MethodsThe cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration. ResultsTalazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models. ConclusionsThe therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment.

Identification of [1,2,4]Triazolo[4,3-a]pyrazine PARP1 inhibitors with overcome acquired resistance activities

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors can selectively kill homologous recombination (HR) deficient cancer cells and elicit anticancer effect through a mechanism of synthetic lethality. In this study, we designed, synthesized and pharmacologically evaluated a series of [1,2,4]triazolo[4,3-a]pyrazine derivatives as a class of potent PARP1 inhibitors. Among them, compounds 17m, 19a, 19c, 19e, 19i and 19k not only displayed more potent inhibitory activities (IC50s < 4.1 nM) than 9 and 1 against PARP1, but also exhibited nanomolar range of antiproliferative effects against MDA-MB-436 (BRCA1−/−, IC50s < 1.9 nM) and Capan-1 (BRCA2−/−, IC50s < 21.6 nM) cells. Notably, 19k significantly inhibited proliferation of resistant Capan-1 cells (IC50s < 0.3 nM). Collectively, the newly discovered PARP1 inhibitors act as a useful pharmacological tool for investigating the mechanism of acquired resistance to PARP1 inhibitors, and may also represent promising therapeutic agents for the treatment of HR deficient cancers with the potential to overcome the acquired resistance.

Blue LED induced three component reactions for the generation of 4, 6-dioxo-hexahydro-1H-furo[3, 4-c] pyrrole: Their evaluation as anticancer agents through PARP inhibition.

Herein we report a catalyst, metal and additive free generation of carbonyl ylides by blue LED irradiation of aryl diazoacetates in presence of aldehydes. The resulting ylides underwent [3+2] cycloaddition with substituted maleimides present in the reaction mixture to afford 4, 6-dioxo-hexahydro-1H-furo[3, 4-c] pyrrole in excellent yields. Fifty compounds were synthesized based on this scaffold. Molecular docking indicated them to be potential poly ADP ribose polymerase (PARP) inhibitor. Screening a representative member of the library against PARP enzyme revealed a few potential inhibitors with IC50 of 600-700 nM. The phenotypic screening against MCF7, A549 and HePG2 cells furthermore indicated that these compounds selectively inhibit the proliferation of A549, HeLa and HePG2 cells with IC50 of 1 - 2 mM. The mechanism of action of the most active compound at the cellular level was investigated.

Alliance A021804: A prospective, multi-institutional phase II trial evaluating temozolomide versus temozolomide and olaparib for advanced pheochromocytoma and paraganglioma.

TPS4191 Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors (NETs) that arise from chromaffin cells. Few antitumor therapies have been developed for patients (pts) with advanced PHEO/PGLs (APP). Potent poly (ADP-ribose) polymerase (PARP) is activated after DNA damage and regulates base excision repair, homologous recombination and non-homologous end joining. Inhibition of PARP enzymatic activity blocks PARP-mediated DNA repair, therefore PARP inhibitors can be directly cytotoxic to tumor cells which then permits synergy with agents that increase prevalence of single-strand breaks in tumor models. Temozolomide (TMZ) is an alkylating agent that induces single-strand DNA breaks and therefore is an optimal therapeutic pair with a PARP inhibitor. We are conducting a phase II multi-institutional study to evaluate the antitumor activity of TMZ and olaparib [OLA (a PARP inhibitor)] in patients with APP. Methods: Patients with APP with radiographic evidence of disease progression by RECIST v1.1 in the 12 months prior to registration can be enrolled in this phase II randomized study. Patients will be randomized in a 2:1 allocation with more patients to Arm 1. Arm 1 will receive TMZ 75 mg/m2 daily and OLA 200 mg twice daily on days 1-7 of a 21-day cycle. Arm 2 will receive TMZ 200 mg/m2 daily on days 1-5 of a 28-day cycle. Treatment on Arm 1 will continue for 13 cycles, followed by OLA maintenance until disease progression. Treatment on Arm 2 will continue for 13 cycles or until disease progression. The primary objective is to compare the progression-free survival between the two arms with a planned interim analysis for futility. Secondary endpoints include safety, response rate, and overall survival. Correlative endpoints include biochemical response and biomolecular markers (germline succinyl dehydrogenase mutations and tumor status of the repair enzyme methylguanine-DNA methyltransferase). We anticipate a null PFS median of approximately 5.4 months. We plan to accrue a total of 76 patients (randomized at a rate of 2:1 with more patients enrolled to the TMZ+OLA arm) in 38 months with a minimum follow-up of 2.5 months to achieve 56 PFS events. This design includes one interim analysis for futility using Rho Family spending functions (Rho = 2.5) and will yield 89% power to detect a hazard ratio (HR) of 0.5 (median PFS of 5.4 vs. 10.8 months) assuming exponential survival and using a one-sided log-rank test with type I error rate of 0.11. Clinical trial information: NCT04394858 .

In-silico method for elucidation of prodigiosin as PARP-1 inhibitor a prime target of Triple-negative breast cancer

Triple-Negative Breast Cancer (TNBC) is found to be one of the life-threatening cancer. Poly (ADP-Ribose) Polymerase-1 (PARP-1) is overexpressed by those tumour cells, which become resistant to chemotherapies. Inhibition of PARP-1 has a considerable effect on treating TNBC. Prodigiosin is a valuable pharmaceutical compound that exhibits anticancer properties. The present study aims to virtually evaluate prodigiosin as a potent PARP-1 inhibitor using Molecular docking and Molecular Dynamics (MD) simulation studies. The PASS (Prediction of Activity Spectra for Substances) prediction tool evaluated the biological properties of prodigiosin. Then the drug-likeness and pharmacokinetic properties of prodigiosin were determined using Swiss-ADME software. It was suggested that prodigiosin obeyed Lipinski’s rule of five and thus could act as a drug with good pharmacokinetic properties. Moreover, molecular docking was done with AutoDock 4.2 to identify the critical amino acids of the protein–ligand complex. It was indicated that prodigiosin has a docking score of −8.08 kcal/mol, which showed its effective interaction with crucial amino acid, His201A of PARP-1 protein. Further, MD simulation was performed using Gromacs software to validate the stability of the prodigiosin-PARP-1 complex. Prodigiosin was found to have good structural stability and affinity at the active site of PARP-1 protein. Additionally, PCA and MM-PBSA were calculated for the prodigiosin-PARP-1 complex, which revealed that prodigiosin has an excellent binding affinity towards PARP-1 protein. Prodigiosin can possibly be used as oral drug due to its PARP-1 inhibition through high binding affinity, structural stability, and receptor flexibility towards crucial amino acid residue His201A of PARP-1 protein. In-addition, in-vitro cytotoxicity, and apoptosis analysis of prodigiosin-treated TNBC cell line-MDA-MB-231 revealed that prodigiosin exhibited significant anticancer activity in 101.1 µg/mL concentration, when compared to commercially available synthetic drug cisplatin. Thus, prodigiosin could act as a potential candidate for treatment of TNBC than the commercially available synthetic drugs.

Identification of indole-based natural compounds as inhibitors of PARP-1 against triple-negative breast cancer: a computational study

Triple-negative breast cancer (TNBC) is the most aggressive kind of breast cancer known to mankind. It is a heterogeneous disease that is formed due to the missing estrogen, progesterone and human epidermal growth factor 2 receptors. Poly(ADP-ribose) polymerase-1 (PARP-1) protein helps in the development of TNBC by repairing the cancer cells, which proliferate and spread metastatically. To determine the potential PARP-1 inhibitors (PARPi), 0.2 million natural products from Universal Natural Product Database were screened using molecular docking and six hit compounds were selected based on their binding affinity towards PARP-1. The bio-availability and drug-like properties of these natural products were evaluated using ADMET analysis. Molecular dynamics simulations were conducted for these complexes for 200 ns to examine their structural stability and dynamic behaviour and further compared with the complex of talazoparib (TALA), an FDA-approved PARPi. Using MM/PBSA calculations, we conclude that the complexes HIT-3 and HIT-5 (−25.64 and −23.14 kcal/mol, respectively) show stronger binding energies with PARP-1 than TALA with PARP-1 (−10.74 kcal/mol). Strong interactions were observed between the compounds and hotspot residues, Asp770, Ala880, Tyr889, Tyr896, Ala898, Asp899 and Tyr907, of PARP-1 due to the existence of various types of non-covalent interactions between the compounds and PARP-1. This research offers critical information about PARPi, which could potentially be incorporated into the treatment of TNBC. Moreover, these findings were validated by comparing them with an FDA-approved PARPi.

Design, synthesis and molecular modeling study of certain quinazolinone derivatives targeting poly (ADP-ribose) polymerase 1 (PARP-1) enzyme as anti-breast cancer and radio-sensitizers

A novel two series of S-alkylated quinazolinones 4–10 and N-alkylated quinazolinones 11–17 was designed and synthesized as potential PARP-1 inhibitors. Quinazolinone scaffold was used as a bioisostere to the phthalazinone core of Olaparib (reference drug). All the newly synthesized compounds were evaluated for their in vitro cytotoxicity against the human breast cancer MCF-7 cell line. The most active compounds, 10 and 15, with IC50 values of 11.4 µM and 10.6 µM, respectively, which are 2.8 and 3 times higher than Doxorubicin (IC50 32.02 µM), were tested for PARP-1 inhibitory activity and showed IC50 0.17 µM and 0.14 µM, respectively when compared to Olaparib (IC50 0.06 µM). Additionally, the capability of γ-radiation to augment the in vitro cytotoxic activity of 10 and 15 was studied and exhibited an increase in the cell-killing effect at lower concentrations after combining with γ-radiation. A molecular modeling study was performed to investigate the possible binding mode of compounds 10 and 15 in the active site of the PARP-1 enzyme.

Design, synthesis, biological evaluation and molecular docking study of novel urea-based benzamide derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors

Poly(ADP-ribose) polymerase-1 (PARP-1) is one of the key members of DNA repair enzymes that is responsible for the repair of DNA single-strand breaks. Inhibition of PARP-1 has been demonstrated to be a promising strategy to selectively kill tumor cells by targeting DNA repair pathway. Herein, a series of novel urea-based benzamide derivatives were designed and synthesized based on the structure-based drug design strategy. The anticancer activities against five human cancer cell lines including HCT116, MDA-MB-231, HeLa, A579 and A375 were evaluated and the preliminary structure-activity relationships were summarized. Among them, compounds 23f and 27f exhibited potent antiproliferative effects against HCT116 cells with IC50 values of 7.87 μM and 8.93 μM, respectively. Moreover, both compounds displayed excellent PARP-1 inhibitory activities with IC50 values of 5.17 nM and 6.06 nM, respectively. Mechanistic investigations showed that 23f and 27f could effectively inhibit colony formation and cell migration of HCT116 cells. Furthermore, 23f and 27f could cause cell cycle arrest at G2/M phase, and induce apoptosis by upregulating the expression of Bax and cleaved Caspase-3 and downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. In addition, molecular docking studies provided the rational binding modes of these compounds in complex with PARP-1. Collectively, these results suggested that 23f and 27f could serve as promising drug candidates for further investigation.

Combination of ligand and structure based virtual screening approaches for the discovery of potential PARP1 inhibitors.

Poly (ADP-ribose) polymerase 1 (PARP1) has high therapeutic value as biomolecular target for research and development of small molecules with antineoplastic activity, since it is upregulated in many cancers, especially in ovarian and BRCA 1/2 mutated breast cancers. Decades of investigation of PARP inhibitors (PARPi) have led to the approval of several drug compounds, however clinical application of PARPi in cancer therapy is limited due to a number of factors, including low selectivity, weak affinity and undesired side effects. Thus, identification of novel drug-like chemical compounds with alternatives to the known PARPi chemical scaffolds, binding modes and interaction patterns with amino acid residues in the active site is of high therapeutic importance. In this study we applied a combination of ligand- and structure-based virtual screening approaches with the goal of identification of novel potential PARPi.

Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer.

Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.

Development of the PARP inhibitor talazoparib for the treatment of advanced BRCA1 and BRCA2 mutated breast cancer

ABSTRACT Introduction BRCA1 and BRCA2 (BRCA1/2) mutation breast cancers constitute an uncommon, but unique group of breast cancers that present at a younger age, and are underscored by genomic instability and accumulation of DNA damage. Talazoparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor that exploits impaired DNA damage response mechanisms in this population of patients and results in significant efficacy. Based on the results of the EMBRACA trial, talazoparib was approved for the treatment of patients with advanced germline BRCA1/2 mutant breast cancer. Areas covered In this review, the authors highlight the relevant clinical trials of talazoparib, as well as, safety, tolerability, and quality of life considerations. They also examine putative response and resistance mechanisms, and rational combinatorial therapeutic strategies under development. Expert opinion Talazoparib has been a major advance in the treatment of germline BRCA1/2 mutation breast cancer with both clinical efficacy and improvement in quality of life compared to standard cytotoxic chemotherapy. To date, the optimal sequencing of talazoparib administration in the metastatic setting has not yet been established. A deeper understanding of response and resistance mechanisms, and more broadly, the DNA repair pathway, will lead to additional opportunities in targeting this pathway and open up therapeutic indications to a broader patient population.

Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer

ObjectivesVeliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). Materials and methodsPatients received veliparib orally twice daily (BID) in escalating doses (60–240 mg, Day –3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120–240 mg BID, Days –2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. ResultsForty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7–32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0–not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0–not reached). ConclusionsWhen combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

Abstract 2054: Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models

Abstract Objective: Homology-directed repair (HDR) pathway is the major DNA double-strand break repair pathway. BRCA-deficiency impairs this pathway, and combination with Poly(ADP-ribose) polymerase (PARP) inhibition results in cell death. This process is known as “synthetic lethality”. A proportion of breast cancer, ovarian cancer and other solid tumor patients carrying BRCA-mutated gene receive benefits from PARP inhibitors. In this study, we present in vitro activity and in vivo efficacy data of a novel small molecule PARP inhibitor, TQB3823 to support it as our clinical candidate. Method: Enzyme inhibition activities of TQB3823 were determined in PARP1/PARP2/Tankyrase 1 assays. Cellular anti-proliferative activity and selectivity were evaluated in MDA-MB-436 cell line with BRCA1 mutation and BRCA wild type MDA-MB-231 cell line. Antitumor efficacy of TQB3823 was investigated in BRCA1 mutated MDA-MB-436 breast cancer CDX model. Result: TQB3823 showed high potency and selectivity at both enzymatic and cellular level. IC50 of TQB3823 in PARP1/PARP2/Tankyrase 1 assays are 2.8/0.9/629.3 nM, respectively. It inhibited proliferation of BRCA1 mutant MDA-MB-436 cell with IC50 of 9.6 nM. In contrast, TQB3823 showed little anti-proliferative activity in BRCA-wild type MDA-MB-231 cell with IC50 &amp;gt;10 μM. TQB3823 demonstrated antitumor efficacy in dose dependent fashions with tumor regression was observed at 25 mg/kg in MDA-MB-436 CDX model. The level of antitumor effects was superior to niraparib at the same dose in the same study. DNA trapping experiments revealed similar potency to olaparib indicative of low toxicity. Conclusion: We have identified a novel, potent and selective PARP inhibitor TQB3823, which inhibits the proliferation of BRCA mutant cells but spares the wild type cells. In vivo study in a BRCA-deficiency tumor model confirms the high in vivo efficacy of this molecule. In conclusion, TQB3823 represents a promising differentiated clinical candidate for treating solid cancers with homology directed repair. Citation Format: Hu Yanbin, Zhang Xiquan, Yang Ling, Tian Xin, Li Gang, Hu Lihong, Charles Z. Ding, Xia Yuanfeng, Li Wei, Yin Shanshan, Chen Ying, Wu Songliang, Chen Shuhui. Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2054.

Integrated support vector machine and pharmacophore based virtual screening driven identification of thiophene carboxamide scaffold containing compound as potential PARP1 inhibitor

Poly (ADP-ribose) polymerase-1 (PARP1) inhibition strategy for cancer treatment is gaining advantage particularly in patients having a mutation in BRCA1/BRCA2 gene. To date, four drugs have obtained FDA approval and some inhibitors are in clinical trials. To identify more potent PARP1 inhibitors extensive research is going on to enrich the library of PARP1 inhibitors with compounds belonging to different classes. We employed an integrated virtual screening approach to identify potential PARP1 inhibitors. The sequential support vector machine (SVM) and pharmacophore model based virtual screening was carried out on the Maybridge library. The obtained hits were docked in the binding site of the PARP1 catalytic domain and nine drug-like compounds showing good ADME properties and form critical molecular interactions with the binding site residues were considered for the in vitro PARP1 inhibition assay. MD simulations were performed to decipher the stability of the PARP1-ligand complexes. Hydrogen bond interactions were also probed for their stability during MD simulations. We have identified three compounds (BTB02767, GK01172, and KM09200) showing 50% inhibition of PARP1 enzyme activity at 25 μM. BTB02767 and KM09200 have phthalazinone scaffold, while GK01172 bears a thiophene carboxamide scaffold, which could be a new chemotype of PARP1 inhibitors. In conclusion, GK01172 may serve as an important compound for further development of PARP1 inhibitors containing thiophene carboxamide scaffold. Communicated by Ramaswamy H. Sarma

TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC).

93 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (a potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned interim analysis (IA; Dec 2019). Updated results at a Sep 4 2020 cut-off, available in November 2020, will be presented at the meeting. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal, or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to objective response; response duration; prostate-specific antigen (PSA) decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and &lt;5 per 7.5 mL blood); time to PSA progression; radiographic progression-free survival (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed. Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cut-off Dec 12 2019); 75 pts were evaluable for IA, with DDRm, had measurable disease, received ≥16 weeks’ treatment, and were assessed for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All pts evaluable for IA had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Funding: Pfizer Inc. Clinical trial information: NCT03148795. [Table: see text]

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models.