P1/2, N=66, Recruiting, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Recruiting

Mechanistically, Niraparib facilitates BTZ-induced ROS elevation, causing DNA double-strand breaks (DSBs), and simultaneously inhibits lesion repair by impeding the expression of repair proteins XRCC1 (X-ray repair cross-complementing protein 1)and POLβ (DNA polymerase beta). Overall, Niraparib plus bortezomib represent a promising approach for treatment of MM.

P2, N=30, Recruiting, Mayo Clinic | Trial completion date: Dec 2025 --> Sep 2025 | Trial primary completion date: Dec 2025 --> Sep 2025

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

P2, N=30, Recruiting, Mayo Clinic | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Dec 2025

Compounds 1 and 2 were further investigated using in vitro cell viability assays, which revealed that cells treated with either lead PARP inhibitor and cisplatin in combination had significantly lower survival rates than those treated with cisplatin alone. At 10 µM, the combination showed more significant cell survival reduction, suggesting greater inhibition of PARP increases lethality, particularly in HeLa and PC-3 cell lines at 96 h and beyond.

The most active compounds were shown to retain selectivity toward PARP1, despite the reduced inhibition potency in the presence of histone PARylation factor 1 (HPF1) capable of regulating PARP1/PARP2 catalytic activity and ADP-ribosylation reaction specificity. The inhibitors obtained seem to be promising for further research as potential drugs.

P2, N=130, Recruiting, Fudan University | Not yet recruiting --> Recruiting | Initiation date: Jul 2024 --> Sep 2024

P1, N=54, Not yet recruiting, EMD Serono Research & Development Institute, Inc.

P1, N=8, Not yet recruiting, AstraZeneca

30 achieved tumor regression in the BRCA1-mutated MDA-MB-436 xenograft model and showed synergistic efficacy in combination with carboplatin in the SUM149PT xenograft model. In the rat hematological toxicity study, 30 exhibited minimal impact on hematological parameters at 25 mg/kg, while AZD5305 at 1 mg/kg caused 56.5% reduction of reticulocyte. Taken together, we discovered compound 30 with a therapeutic index superior to that of PARP1 inhibitors AZD5305 and AZD9574 in the preclinical setting.

P1/2, N=66, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.

P1, N=90, Recruiting, Duke Street Bio Ltd | Not yet recruiting --> Recruiting

P1, N=54, Recruiting, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Recruiting

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Feb 2025 --> Nov 2025 | Trial primary completion date: Feb 2025 --> Nov 2025

P3, N=500, Recruiting, AstraZeneca | Trial completion date: Jul 2030 --> Oct 2030

These compounds exhibited target-specific and strong binding profiles, with docking scores of -7.17, -7.41, and -7.37 kcal/mol, respectively, and MM/GBSA scores of -52.51, -43.77, and -62.87 kcal/mol, respectively. These novel compounds (DDNO derivatives) hold promise as potential PARP-1 inhibitors for the development of targeted therapeutics against cancer.

Collectively, our systematic efforts to design lead-like molecules have the potential to open doors for the exploration of dual PARP1-BRD4 inhibitors as a promising avenue for breast cancer treatment. Furthermore, the developed approach can be extended to systematically design inhibitors targeting PARP1 and other related targets.

P1, N=52, Terminated, Nerviano Medical Sciences | N=150 --> 52 | Trial completion date: Dec 2024 --> May 2024 | Active, not recruiting --> Terminated; The study closure is related to sponsor decision to shift towards the clinical development of NMS-03305293 in combination in a broader range of indication and not based on emerging safety or efficacy concerns.

We also show that the novel brain penetrant, PARP1-selective inhibitor AZD9574 compares favorably to olaparib when combined with RT, prolonging survival in a syngeneic orthotopic model of H3K27M DMG. This study highlights the ability of PARP1 inhibition to radiosensitize and induce an NK cell-mediated antitumor immunity in H3K27M DMG and supports future clinical investigation.

Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.

P3, N=500, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting | Initiation date: Apr 2024 --> Aug 2024

P1, N=70, Recruiting, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Recruiting

In addition, molecular docking study demonstrated that the binding mode of 9b with PARP-1 was similar to that of niraparib, forming multiple hydrogen bond interactions with the active site of PARP-1. Taken together, these findings suggest that 8-carbamyl-3-arylcoumarin scaffold could serve as an effective structural unit for PARP-1 inhibition and offer a valuable paradigm for the structural modification of natural products.

P2, N=130, Not yet recruiting, Fudan University

P1, N=54, Not yet recruiting, EMD Serono Research & Development Institute, Inc.

"Foundation Medicine, Inc. today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for FoundationOne Liquid CDx to be used as a companion diagnostic for AKEEGA (niraparib and abiraterone acetate) from Janssen Biotech, Inc, a Johnson & Johnson company, the first and only FDA-approved dual-action tablet combining PARP inhibition and hormone therapy for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC)."

These data suggest that the combination of donafenib and a PARP1 inhibitor results in more significant DNA damage in cells and promotes cell apoptosis. Thus, the combination of donafenib and PARP1 inhibitors has the potential to be a treatment option for liver cancer.

Triple combinations of KDM inhibitors with cisplatin and olaparib exhibited the best cytotoxic activity, which was associated with DNA damage accumulation and altered expression of genes associated with apoptosis induction and cell cycle arrest. In conclusion, triple combinations of KDM inhibitors (especially GSK-J4 and JIB-04) with cisplatin and olaparib represent a promising strategy for head and neck cancer treatment.

In combination studies, Senaparib used with temozolomide (TMZ) had shown strong synergistic cytotoxicity in both in vitro and in vivo experiments. Senaparib represents a novel class of PARP1 inhibitors that can be used for the treatment of cancer. A phase III clinical study of Senaparib for maintenance treatment following first-line chemotherapy in patients with advanced ovarian cancer has met its primary endpoint, and a new drug application of Senaparib has been accepted by National Medical Products Administration (NMPA) of China for review.

P1, N=16, Completed, AstraZeneca | Active, not recruiting --> Completed

P1, N=90, Not yet recruiting, Duke Street Bio Ltd

In vivo, in a xenograft model, 5d effectively reduced tumor growth by downregulating PARP1 expression. Overall, compound 5d shows promise as a potential therapeutic agent for the treatment of BRCA wild-type breast cancer.

Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.

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.

P1, N=70, Not yet recruiting, EMD Serono Research & Development Institute, Inc.

P1, N=23, Completed, Rhizen Pharmaceuticals SA | Active, not recruiting --> Completed

P1, N=76, Recruiting, Synnovation Therapeutics, Inc. | Not yet recruiting --> Recruiting

P3, N=500, Not yet recruiting, AstraZeneca

P1/2, N=298, Recruiting, Acerand Therapeutics (Shanghai) Limited

P1, N=150, Active, not recruiting, Nerviano Medical Sciences | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2024

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.