In addition, CETSA revealed that PARP1 is an important target gene for the inhibition of HEL cell growth, and SGP-17-S exerted its action on leukemia cells by targeting PARP1. Therefore, this study might provide new solutions and ideas for the treatment of leukemia.

P1/2, N=54, Recruiting, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Recruiting

P1/2, N=490, Recruiting, AstraZeneca | Trial primary completion date: Apr 2025 --> Jan 2026

In vivo analysis results revealed that 4F-DDC inhibited the growth of HCC-1937-derived tumor xenografts, possibly via the induction of DNA damage and activation of the cGAS-STING pathway. In summary, the current study provides a new perspective on the antitumor mechanism of PARP inhibitors and showcases the therapeutic potential of 4F-DDC in the treatment of breast cancer.

Besides, the impact of compounds 3a-e and 4b on the activity of PARP-1 was investigated, where 3c, 3d, and 3e demonstrated comparable efficiencies to olaparib...In addition, a significant inhibition of cell proliferation and a remarkable 15 to 50-fold reduction in the number of colonies compared to the control group were recorded. Finally, the PARP-1 inhibitory potential of the novel hybrids was compared to the co-crystal of the target receptor (PDB ID: 6NTU) using molecular docking.

P1/2, N=150, Recruiting, Nerviano Medical Sciences | N=75 --> 150

Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells' resistance to them.

P1/2, N=54, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.

P1, N=23, Active, not recruiting, Rhizen Pharmaceuticals SA | Trial primary completion date: Dec 2023 --> Mar 2024

P1, N=18, Completed, Jiangsu HengRui Medicine Co., Ltd. | Active, not recruiting --> Completed

P1/2, N=165, Recruiting, Valerio Therapeutics

P1/2, N=70, Recruiting, Eikon Therapeutics

Niraparib + F7 treatment led to cell cycle arrest and endoplasmic reticulum (ER) stress, inhibited cell migration, reduced the % of ALDH positive cells in the population and enhanced PARP1 cleavage. The synergistic effect of the niraparib + F7 may result from the treatment affecting multiple genetic pathways involving cell death and reducing mesenchymal characteristics.

P1, N=76, Not yet recruiting, Synnovation Therapeutics, Inc.

P1, N=18, Active, not recruiting, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Active, not recruiting

P1, N=18, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.

P1, N=248, Recruiting, Gilead Sciences | Not yet recruiting --> Recruiting

Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC.

P3, N=1800, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1/2, N=490, Recruiting, AstraZeneca | N=270 --> 490 | Trial primary completion date: Sep 2024 --> Apr 2025

The Phase 3 PROpel study showed that first-line combination treatment with olaparib and abiraterone significantly improved radiographic progression-free survival (rPFS) over abiraterone alone in pts with metastatic castration-resistant PC (mCRPC) (hazard ratio [HR], 0.66; 95% CI, 0.54 to 0.81; p<0.001). Similarly, the Phase 3 TALAPRO-2 study showed that first-line talazoparib with enzalutamide resulted in statistically significant improvement in rPFS over enzalutamide alone in pts with mCRPC (HR, 0.63; 95% CI, 0.51 to 0.78; p<0.0001)...Enrollment began in September 2023; sites across North America, Europe and Australia will enroll up to 120 patients. Clinical trial information: NCT05938270.

PETRANHA, an open-label nonrandomized study, is evaluating the safety and DDIs of AZD5305 with physician’s choice of NHA (enzalutamide [enza], abiraterone acetate [abi] or darolutamide [daro]) in pts with metastatic prostate cancer...Key exclusion criteria were previous PARPi, platinum chemotherapy, or targeted radioligand therapy for pts with mCRPC or mCSPC; and previous NHA or docetaxel in pts with mCSPC... Initial safety, tolerability, and DDI data from the PETRANHA study indicates that AZD5305 can be safely combined with three individual NHAs with low rates of dose interruptions or reductions. The study is ongoing in Australia, Italy, UK, and USA. Clinical trial information: NCT05367440.*Includes AZD5305 in combination with any NHA.

P1, N=248, Not yet recruiting, Gilead Sciences

P1b | "Venadaparib in combination with irinotecan showed synergistic effect in vitro assays and promising clinical efficacy in the systemic treatment of refractory GC, particularly in patients with HRD. The dose expansion phase of the study is ongoing to investigate the optimal biological dose and patient selection strategies, in a randomized design. Clinical trial information: NCT04725994."

When AIL is paired with a PARP1 inhibitor, olaparib (OLP), drug sensitivity improves...This study proves that the inhibitory effect of AIL on BRCA1 allowed even cancer cells with normal BRCA1 function to be sensitive to PARP inhibitors when it is simultaneously administered with OLP. The results greatly expanded the scope of the application of PARPi.

When tested against the HepG2 cell line, compound I, and compound II both had significantly increased cytotoxic activity when compared to the reference medication 5-Fluorouracil (5-FU), with IC values of 1.43 M, 5.32 M, and 6.52 M for compound 1, 5-FU and compound II, respectively...Therefore, compound I shows promise as a selective anti-cancer derivative for the treatment of liver cancer after more investigations and clinical studies. This selectivity is a favorable characteristic in the developing cytotoxic agents for cancer treatment, as it indicates a potential for reduced harm to health tissues.

P1/2, N=804, Recruiting, AstraZeneca | N=604 --> 804

Finally, the level of PARP1 activity at R loops correlated with PARPi sensitivity, suggesting that R-loop associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer.

The combination of three key features - PARP1 selectivity, PARP1 trapping profile, and high CNS penetration in a single molecule, supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anti-cancer efficacy both as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594).

P3, N=1800, Not yet recruiting, AstraZeneca

P1/2, N=39, Terminated, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | N=78 --> 39 | Trial completion date: Apr 2024 --> Jul 2023 | Recruiting --> Terminated | Trial primary completion date: Jan 2024 --> Jul 2023; The sponsor voluntarily terminated the study

Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.

P1/2, N=96, Not yet recruiting, Fujian Cancer Hospital

P1, N=318, Recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

Then, hierarchical docking studies were performed to further screen the compounds and evaluate the ligands binding mode, whose putative dual-target mechanism of action was investigated through the correlation between the antiproliferative activity data and the target proteins' (CDK-1 and PARP-1) expression pattern. Finally, a Molecular Dynamics Simulation confirmed the high stability of the most effective selected compound 645656 in complex with both PARP-1 and CDK-1.

No abstract available

These effects result from a strong interplay between ETS transcription factors and the PARP-1 enzyme. This review summarises the existing knowledge of this molecular interaction and discusses the promising therapeutic applications.

All the synthesized compounds have a better docking score than niraparib (-9.05). Further, the synthesized compounds have a favorable ADME profile. Therefore, they may serve as important leads in discovering PARP-1 inhibitors.

P1/2, N=75, Recruiting, Nerviano Medical Sciences | N=125 --> 75

Compound 6 exerted stronger PARP1 inhibitory activity and anti-cancer activity as compared to olaparib in BRCA1-mutated TNBC cells and TNBC patient-derived organoids. In addition, we demonstrated that compound 6 enhanced the sensitivity of BRCA1-mutated and wild-type TNBC cells to chemotherapy including paclitaxel and cisplatin. Collectively, our study identified a novel PARP1 inhibitor, providing a therapeutic candidate for the treatment of TNBC.

While responses were seen in patients with EWS, the combination of the PARP1/2 inhibitor talazoparib with irinotecan and/or temozolomide did have a narrow therapeutic window with concern for hematologic toxicity. DNA damaging agents combined with PARPi have shown effect both preclinically and clinically in EWS; however, the narrow therapeutic window represents a significant challenge in treating patients. The combination of nal-IRI with talazoparib is currently being tested in early phase pediatric trials as one strategy to improve tolerability as nal-IRI combinations were shown in adult studies to have less grade 3/4 dose-limiting toxicities. The development of PARP1 selective agents such as AZD5305 may further mitigate toxicity and allow for dose escalation and potentially improved therapeutic benefit in this patient population.