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

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

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

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

Discovery of tricyclic PARP7 inhibitors with high potency, selectivity, and oral bioavailability. (PubMed, Eur J Med Chem) - "Importantly, daily treatment of 30 mg/kg of 8 induced 81.6 % tumor suppression in NCI-H1373 lung xenograft mice tumor models, which is significantly better than the clinical candidate, RBN-2397. These intriguing features highlight the promising advantages of 8 as an antitumor agent."

Journal • Lung Cancer • Oncology • Solid Tumor • TIPARP

Discovery of Highly Selective PARP7 Inhibitors with a Novel Scaffold for Cancer Immunotherapy. (PubMed, J Med Chem) - "Herein, we employed a rigid constraint strategy (reduction in molecular flexibility) to design and synthesize a series of novel indazole-7-carboxamide derivatives based on the structure of RBN-2397...In the CT26 syngeneic mouse model, monotherapy with (S)-XY-05 displayed a strong antitumor effect (TGI: 83%) by activating T-cell-mediated immunity within the tumor microenvironment. Collectively, we confirmed that (S)-XY-05 has profound effects on tumor immunity, which paves the way for future studies of PARP7 inhibitors that could be utilized in cancer immunotherapy."

Journal • Oncology • TIPARP

PARP7-mediated ADP-ribosylation of FRA1 promotes cancer cell growth by repressing IRF1- and IRF3-dependent apoptosis. (PubMed, Proc Natl Acad Sci U S A) - "Loss of FRA1 ADP-ribosylation via PARP7 inhibition by RBN-2397 or mutation of the ADP-ribosylation site C97 increased FRA1 degradation by the proteasome via PSMC3...Furthermore, high PARP7 expression was indicative of the PARP7 inhibitor response in FRA1-positive lung and breast cancer cells. Collectively, our findings highlight the connected roles of PARP7 and FRA1 and emphasize the clinical potential of PARP7 inhibitors for FRA1-driven cancers."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CASP8 • FRA1 • IRF1 • TIPARP

ANTI-TUMOR ACTIVITY OF PARP7 INHIBITOR RBN-2397 IN SOFT-TISSUE SARCOMAS (CTOS 2023) - "The immune-high group characterized by the presence of B cell rich tertiary lymphoid structures (TLS) demonstrated improved survival and a high response rate to PD-1 blockade by pembrolizumab...To deepen the mechanism of action, we also analyzed the DNA damages in situ by STRIDE technique and found that PARP7 inhibition induces dsDNA breaks in nucleus but also in cytoplasm in some cell lines and that the combination with doxorubicin or trabectedin increased the DNA damages content (Figure 1)... PARP7 inhibition has anti-tumor activity in soft-tissue sarcomas through cell cycle inhibition and induction of DNA damage. Interestingly, the combination with PARP7 inhibition increases the efficacy of chemotherapy already used in sarcoma management providing a clear rationale for its clinical investigation in this indication."

Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • TIPARP

ANTI-TUMOR ACTIVITY OF PARP7 INHIBITOR RBN-2397 IN SOFT-TISSUE SARCOMAS (CTOS 2023) - "To assess whether PARP7 inhibition can influence the efficacy of chemotherapy in STS cells, we performed viability assays in combination with either doxorubicin or trabectedin in 10 STS cell lines. PARP7 inhibition has anti-tumor activity in soft-tissue sarcomas through cell cycle inhibition and induction of DNA damage. Interestingly, the combination with PARP7 inhibition increases the efficacy of chemotherapy already used in sarcoma management providing a clear rationale for its clinical investigation in this indication."

Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • TIPARP

RBN-2397, a novel PARP7 inhibitor, in combination with chemotherapy leads to increased Type I interferon (IFN) signaling and improved in vivo efficacy in murine models (SITC 2023) - No abstract available

Combination therapy • Preclinical • Oncology • TIPARP

RBN-2397 in Combination With Pembrolizumab in Patients With SCCL (clinicaltrials.gov) - P1b/2 | N=50 | Active, not recruiting | Sponsor: Ribon Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

Design, synthesis and structure-activity relationship of novel pyridazinone-based PARP7/HDACs dual inhibitors for cancer treatment (ACS-Fall 2023) - "Our results demonstrated that dual PARP7/HDACs inhibitors 8 and 11 could unleash stronger tumoral IFN signaling in numerous cancer cell lines than PARP7 inhibitor clinical candidate RBN-2397...Structure IC50 of compounds 4~11 against HDAC1 and 6 and PARP7Figure 2. The influence of compounds on INF-β production"

Oncology • HDAC1 • TIPARP

RBN-2397 in Combination With Pembrolizumab in Patients With SCCL (clinicaltrials.gov) - P1b/2 | N=50 | Recruiting | Sponsor: Ribon Therapeutics, Inc. | Trial completion date: Aug 2024 ➔ Dec 2023 | Trial primary completion date: May 2023 ➔ Nov 2023

Combination therapy • Trial completion date • Trial primary completion date • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

First-in-class first-in-human phase 1 trial and translational study of the mono(ADP-ribose) polymerase-7 (PARP7) inhibitor RBN-2397 in patients with selected advanced solid tumors (AACR 2023) - P1b/2 | "RBN-2397 was well tolerated at biologically active drug exposures, with preliminary antitumor activity observed. Paired tumor biopsy translational studies demonstrated the immunomodulatory mechanism of RBN-2397 and support the ongoing trial of RBN-2397 in combination with pembrolizumab (NCT05127590)."

Clinical • IO biomarker • Metastases • P1 data • Breast Cancer • Head and Neck Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • GZMB • LAG3 • PD-1 • PD-L1 • SMARCB1 • TIPARP

Potentiation of Type I interferon signaling leads to in vivo efficacy achieved with combination of chemotherapy and the PARP7 inhibitor RBN-2397 (AACR 2023) - "We tested the ability of platinum (cisplatin, oxaliplatin, and carboplatin) and taxane (docetaxel and paclitaxel) chemotherapy agents to activate the Type I IFN response in the CT26 mouse colon cancer cell line in vitro by gene expression analysis of several ISGs (CXCL10, CCL5, MX1, IFIT1, and IFN-β). Finally, we performed an efficacy study in CT26 tumor bearing mice and observed that the combination of cisplatin and RBN-2397 increased tumor growth inhibition and survival relative to single agent activity. This study provides rationale for exploration of DNA damaging agents in combination with RBN-2397."

Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CXCL10 • IFIT1 • IFNB1 • MX1 • STING • TIPARP

Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells. (PubMed, Cancer Res Commun) - "RBN2397 treatment also induces trapping of PARP7 in a detergent-resistant fraction within the nucleus, which is reminiscent of how inhibitors such as talazoparib affect PARP1 compartmentalization. RBN2397 is a potent and selective inhibitor of PARP7 that reduces the growth of prostate cancer cells, including a model for treatment-emergent neuroendocrine prostate cancer. RBN2397 induces PARP7 trapping on chromatin, suggesting its mechanism of action might be similar to clinically used PARP1 inhibitors."

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

Phase 1 Study of RBN-2397, an Oral PARP7 Inhibitor, in Patients With Solid Tumors (clinicaltrials.gov) - P1 | N=130 | Recruiting | Sponsor: Ribon Therapeutics, Inc. | Trial completion date: Jan 2023 ➔ Jul 2023 | Trial primary completion date: Dec 2022 ➔ Jun 2023

Trial completion date • Trial primary completion date • Breast Cancer • Head and Neck Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ER • HER-2 • PGR • TIPARP