atamparib (RBN-2397) / Ono Pharmaceutical, Nerviano Medical Sciences - LARVOL DELTA

A Phase Ib/II Study of Atamparib, a PARP7 Inhibitor, in Patients With Advanced Solid Tumors (IASLC-WCLC 2026) - "Dose escalation uses a Bayesian Optimal Interval (BOIN) design with backfilling to evaluate three dose levels (200, 250, and 300 mg). After RP2D selection, expansion will enroll four NSCLC adenocarcinoma cohorts: 1) non-G12C KRAS mutations, 2) KRAS G12C inhibitor-naïve, 3) KRAS G12C inhibitor-pretreated, and 4) KRAS wild-type."

Clinical • IO biomarker • Metastases • P1/2 data • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • TIPARP

PARP7: Atamparib in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=178 | Recruiting | Sponsor: Nerviano Medical Sciences (Shanghai) Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

NAD+ Metabolism Licenses Zygotic Genome Activation via PARP7-Mediated ADP-Ribosylation of UHRF1 in Mouse Early Embryos. (PubMed, Adv Sci (Weinh)) - "Genetic knockdown via trim-away technology or pharmacological inhibition with RBN-2397 caused developmental delay/arrest at the 2-cell stage, impaired blastocyst formation, and defective ZGA...This modification stabilized UHRF1 protein (cycloheximide chase), and UHRF1 overexpression partially rescued the transcriptional defects associated with ZGA from PARP7 inhibition. Our findings establish a metabolic-epigenetic axis wherein NAD+ metabolism, via PARP7-mediated ADP-ribosylation of UHRF1, regulates chromatin remodeling and transcriptional activation during ZGA, offering fundamental insights into early development."

Journal • Preclinical • Developmental Disorders • TIPARP • UHRF1

Pharmacological polarization of tumor-associated macrophages toward a CXCL9 antitumor phenotype (CIMT 2026) - "The platform was evaluated in tumor-bearing mice, where biodistribution and cellular targeting were quantified by flow cytometry, and intravital window-chamber imaging assessed CDNP accumulation and CXCL9Hi induction in TAM populations across two tumor models...Screening identified R848 (TLR7/8 agonist), MSA-2 (STING agonist), and RBN2397 (PARP7 inhibitor) as the most potent inducers, increasing CXCL9 expression ~8-fold compared with Interferon-γ control...Tumor growth experiments showed complete remission lasting 60 days without significant weight loss, whereas free drug administration caused pronounced toxicity. These data demonstrate that CDNPs enable systemic, selective delivery of immunomodulators to TAMs and support strong induction of a CXCL9Hi phenotype, resulting in tumor control with favourable tolerability."

IO biomarker • Brain Cancer • Glioma • Oncology • Solid Tumor • CXCL10 • CXCL9 • IFNG • IL12A • TIPARP

A novel PARP7 inhibitor exhibits dual antitumor activity through immune activation and tumor-intrinsic growth inhibition (AACR 2026) - "Notably, across both mechanisms, compound 1 demonstrated comparable or superior activity to RBN2397, a PARP7 inhibitor under clinical evaluation. In summary, our findings highlight PARP7 inhibition as a promising therapeutic strategy that integrates immune activation with tumor-intrinsic growth inhibition. The novel PARP7 inhibitor, compound 1, consistently demonstrated this dual mechanism across diverse preclinical models, supporting its potential as a next-generation therapeutic candidate with both immune-mediated and tumor-intrinsic antitumor activity."

IO biomarker • Oncology • TIPARP

Dual mechanisms of PARP7 inhibition driving potent antitumor activity (AACR 2026) - "We have developed a couple of series of novel PARP7 inhibitors, and in this study, we focused on characterizing the molecular features associated with responsiveness to PARP7 inhibitors in parallel with mechanistic studies using the clinical-stage benchmark, RBN-2397. Collectively, our findings demonstrate that PARP7 inhibition elicits a dual mechanism involving ISG induction and intrinsic cytotoxicity, resulting in robust antitumor activity. The key regulatory factors underlying this dual mechanism may serve as potential biomarkers for patient selection in future clinical trials and help identify individuals most likely to benefit from PARP7-targeted therapy."

IO biomarker • Oncology • TIPARP

Atamparib: First-in-class PARP7 inhibitor for treatment of NSCLC adenocarcinoma in monotherapy and in combination with standards of care (AACR 2026) - "By inhibiting PARP7, atamparib induces FRA1 degradation, reactivates IFN-I signaling, and triggers tumor cell death and immune-mediated tumor clearance. Moreover, atamparib increases the activity of several standards of care and targeted drugs in late development in NSCLC when combined with them.Overall, our data shed light on a PARP7 dependency in NSCLC adenocarcinoma context and support atamparib development in this setting, both in monotherapy and in combination with multiple standards of care."

Combination therapy • IO biomarker • Monotherapy • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ER • FRA1 • KRAS • TIPARP

Discovery of a novel and highly selective PARP7 inhibitor for cancer immunotherapy (AACR 2024) - "Notably, HSN002066 and RBN-2397, the only PARP7 inhibitor currently in Ph 1/2 clinical development, displayed differentiated antiproliferative activities in cell line NCI-H1373 (IC50 are 387.8 nM and 15.2 nM, respectively). However, HSN002066 revealed remarkable antitumor effects as monotherapy (TGI 77% at 100 mg/kg) or combination with PD-1 antibody in CT-26 allograft model.The structure of HSN002066 was not presented and will not be disclosed at the time of presentation at AACR meeting."

Oncology • TIPARP

PARP7: Atamparib in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=178 | Not yet recruiting | Sponsor: Nerviano Medical Sciences (Shanghai) Ltd.

New P1/2 trial • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Atamparib in Patients With Advanced Solid Tumors ( PARP7 ) (ChiCTR) - P1/2 | N=178 | Not yet recruiting | Sponsor: Shanghai Eastern Hospital; Nerviano Medical Science Shanghai Ltd.

New P1/2 trial • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Design and Synthesis of KRASG12C Inhibitors for Antitumor Evaluation Harboring Combination Therapy with Nrf2, PARP-7, and Pan-USP Inhibitors to Alleviate Drug Resistance Synergistically. (PubMed, J Med Chem) - "Compared with positive control MRTX849, the synthesized compounds 7g, 7p, 7q, 7r, 7v, and 7y displayed stronger antiproliferative activities against H358 cells with IC50 values of < 1 nM (3D cell culture) and comparable inhibitory potency against KRASG12C...Meaningfully, 7q combined with Nrf2 inhibitor ML385 or PARP7 inhibitor RBN-2397 greatly enhanced the sensitivity of 7q against lung cells (H1373) in vivo. Furthermore, combination therapy of 7q with pan-USP inhibitor PR-619 obtained a statistically significant synergistic inhibition of H1373 cell growth in vitro and in vivo. Our findings indicate that 7q may be a promising drug candidate for the treatment of cancers harboring the KRASG12C mutation, and the results of the combination regimen established a pharmacological foundation for addressing drug resistance."

Journal • Colorectal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • TIPARP

PARP7 and aryl hydrocarbon receptor differentially regulate mammary cancer cell proliferation and STING-induced type I interferon signalling. (PubMed, Cell Oncol (Dordr)) - "These findings highlight the complexity of the interplay among PARP7, AHR and STING-induced IFN signalling in regulating cancer cell proliferation but also suggest that for some cell lines STING activation might increase their sensitivity to the anti-proliferative effects of RBN2397."

Journal • Breast Cancer • Oncology • Solid Tumor • FOSL1 • STING • TIPARP

PARP7: an Emerging Therapeutic Target-Insights into Biological Functions and Advances in Small-Molecule Inhibitor Development. (PubMed, J Med Chem) - "Notably, the selective PARP7 inhibitor RBN-2397 for tumor treatment has entered Phase II trials, highlighting the translational potential of targeting this enzyme...Furthermore, to advance the study of PARP7 inhibitors, we analyze the mechanisms of action and design strategies of existing PARP7 inhibitors as reported in current papers and patents. Additionally, we share our experiences in designing PARP7 inhibitors and present our insights regarding the opportunities and challenges in this pioneering research field."

Journal • Review • Cardiovascular • Infectious Disease • Oncology • TIPARP

Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling. (PubMed, EMBO J) - "Non-conventional ubiquitin conjugation to ADP-ribosyl-cysteine and degradation by the proteasome forms the basis of a negative feedback loop that regulates modules of AR target genes. Our data expand the repertoire of mono-ADP-ribosyltransferases to include gene regulation via highly selective protein degradation."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • TIPARP

PARP7 inhibition combined with radiotherapy overcomes ICI resistance in breast cancer. (SABCS 2024) - "Additional treatment arms were added for 2250L tumor: PARP7i (RBN-2397, 30mg/kg, daily for 10 days), RT+PARP7i, ICI+PARP7i, and RT+ICI+PARP7i. mRNA-sequencing was performed on the four syngeneic NT tumor models or 48h after treatment with RT (8Gy) +/- PARP1/2i (Olaparib, 1uM), using Illumina TruSeq stranded mRNA library prep on a NextSeq2000... Breast cancers that express PARP7 may be targetable with PARP7i in combination with RT/ICI to enhance ISG expression in the tumor microenvironment and overcome ICI resistance. Future studies will characterize the mechanism of this effect and its potential clinical translation."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • PARP1 • TIPARP • TP53

Screening and design of PARP12 inhibitors from traditional Chinese medicine small molecules using computational modeling and simulation. (PubMed, J Biomol Struct Dyn) - "The compound RBN2397 is utilized as a benchmark, and the binding efficacies of the newly identified small molecules are assessed against a spectrum of criteria, encompassing molecular interactions, binding free energy, and extensive post-simulation analyses...Moreover, ADMET profiling meticulously evaluated the pharmacokinetic profiles and physicochemical characteristics of these promising molecules and their projected human physiological impact. These computational studies indicated their potential therapeutic applicability and predicted acceptable safety profile, advocating their further exploration as viable candidates in cancer treatment."

Journal • Oncology • PARP12

PARP7i Clinical Candidate RBN-2397 Exerts Antiviral Activity by Modulating Interferon-β Associated Innate Immune Response in Macrophages. (PubMed, Drug Dev Res) - "In vivo experiments demonstrated that RBN-2397 enhances innate antiviral immunity in mice infected with VSV, resulting in increased serum IFN-β levels, reduced viral loads, and alleviated pulmonary inflammatory responses of the VSV-infected mice. In conclusion, our findings highlight the potential of RBN-2397 as a promising antiviral therapeutic agent for enhancing the IFN-relative antiviral immune defense in host."

Journal • Oncology • IFNA1 • IFNB1 • STAT1 • STAT2 • STING • TIPARP

PARP7 Inhibitors and AHR Agonists Act Synergistically Across a Wide-Range of Cancer Models. (PubMed, Mol Cancer Ther) - "We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by co-treatment with agonists of the Aryl Hydrocarbon Receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397...Both wildtype and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ER • TIPARP

[PREPRINT] RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells (bioRxiv) - "RBN-2397 inhibited PARP7 activity, decreasing α-tubulin MARylation, leading to its stabilization, and reducing cancer cell proliferation and migration. The addition of paclitaxel further enhanced these effects, highlighting a synergistic interaction between the two drugs. Mutating the site of PARP7-mediated MARylation on α-tubulin similarly resulted in microtubule stabilization and decreased cell migration in the presence of paclitaxel."

Preclinical • Preprint • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells. (PubMed, bioRxiv) - "Finally, we observed that combining RBN-2397 and paclitaxel resulted in a more robust inhibition of aggressive ovarian cancer cell phenotypes. Collectively, this study highlighted the potential of targeting PARP7 in combination with established chemotherapeutic agents to enhance treatment efficacy for ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • TIPARP

[PREPRINT] RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells (bioRxiv) - "When ovarian cancer cells were treated with RBN-2397, we observed a decrease in their growth and migration and, interestingly, the effect was intensified upon adding the microtubule stabilizing chemotherapeutic agent, paclitaxel. Mutating the site of PARP7-mediated α-tubulin MARylation similarly resulted in α-tubulin stabilization and decreased cell migration in the presence of paclitaxel. In summary, we demonstrated that PARP7 inhibition decreased α-tubulin MARylation resulting in its stabilization, and ultimately leading to decreased ovarian cancer cell proliferation and migration. Finally, we observed that combining RBN-2397 and paclitaxel resulted in a more robust inhibition of aggressive ovarian cancer cell phenotypes."

Preclinical • Preprint • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment. (PubMed, J Med Chem) - "Furthermore, B3 and C6 displayed significant in vivo antitumor efficacy in a melanoma B16-F10 tumor mouse model, more than 5.3-fold better than BMS-1 (a PD-L1 inhibitor) and RBN-2397 (a PARP7i clinical candidate) at the dose of 25 mg/kg, without observable side effects. These results provide valuable insight and understanding for developing bifunctional conjugates for potential anticancer therapy."

Journal • Melanoma • Oncology • Solid Tumor • IFNG • PD-1 • TIPARP

Discovery of highly potent PARP7 inhibitors for cancer immunotherapy. (PubMed, Bioorg Chem) - "In this study, we reported the identification of a newly found PARP7 inhibitor (XLY-1) with higher inhibitory activity (IC50 = 0.6 nM) than that of RBN-2397 (IC50 = 6.0 nM)...Pharmacodynamic experiments showed that 50 mg/kg XYL-1 could significantly inhibit tumor growth (TGI: 76.5 %) and related experiments showed that XYL-1 could restore type Ⅰ interferon signaling and promote T cell infiltration in tumor tissues. Taken together, XYL-1 shows promise as a potential candidate for developing cancer immunotherapy agents."

Journal • Oncology • TIPARP

Design, synthesis and structure-activity relationship of novel pyridazinone-based PD-L1/PARP7 dual inhibitors for potential cancer therapy (ACS-Sp 2024) - "Poly (ADP-ribose) polymerase 7 (PARP7) inhibitor RBN-2397 is a clinical stage drug for potential treatment of various cancers...Figure 1. Design of PD-L1/PARP7 dual inhibitors."

Oncology • TIPARP

Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition. (PubMed, J Med Chem) - "Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • TIPARP