HRO761 / Novartis - LARVOL DELTA

Identifying synthetic lethality targets in DDX41-mutated MDS/AML (AACR 2025) - "In DDX41-knockout HeLa cells, treatment with WRN inhibitors NSC 617145 and HRO761 significantly reduced cell growth compared to WT controls...Future studies aim to elucidate the molecular mechanisms underlying SL interactions between DDX41 and its partners, providing insights into the therapeutic potential of targeting these vulnerabilities. This work offers a promising avenue for developing novel treatments for MDS/AML patients harboring DDX41 mutations, ultimately improving clinical outcomes."

Synthetic lethality • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • DDX23 • DDX41 • WRN

Biochemical tools to characterize specific Werner syndrome helicase inhibitors and accelerate drug discovery (AACR 2025) - "Using clinical-stage WRN helicase inhibitor HRO761 and VVD214, we present a complete MOA study demonstrating that the assays generated by Eurofins Discovery teams are well suited for WRN drug discovery project. This demonstration provides strong evidence that the developed assays are well suited for helicase drug candidate discovery, development and characterization. These will help providing innovative solution to fight against cancer an especially the one involving WRN over expression."

Oncology • WRN

Discovery of WRN helicase inhibitors that covalently engage a novel, induced allosteric site (AACR 2025) - "The two clinical-stage WRN inhibitors, HRO761 and RO7589831, both bind in an allosteric pocket near the interface of the two helicase domains (D1 and D2). Whole-genome CRISPR modifier screens with Compound C and a close analog of HRO761 in HCT116 and KM12 cells showed generally concordant functional genomic profiles, with perturbations in SMARCAL1, HELLS, and WDR76 enriched and POLQ and RBM6 depleted by WRN inhibition. In conclusion, we report a series of WRN inhibitors that engage a novel cryptic binding site and show a distinct mechanism of inhibition to WRN inhibitors currently in clinical development."

Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • BRIP1 • MSI • POLQ • RBM6 • RECQL • RECQL4 • RECQL5 • WRN

Studying WRN inhibitors with dSTRIDE-WRN assay [WITHDRAWN] (AACR 2025) - "WRN inhibitors, such as HRO761, exploit the synthetic lethality of MSI-H cancers by trapping WRN on DNA, inducing genomic instability, and selectively killing tumor cells...By providing a direct readout of WRN's enzymatic function, the assay offers valuable insights into the molecular mechanisms underlying WRN-targeting therapies. This platform holds the potential for advancing the development and evaluation of WRN inhibitors in MSI-H cancers and beyond."

Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

SNV5686 a differentiated inhibitor of Werner helicase with potent activity against both WT WRN and WRN-C727S mutant proteins for treatment of MSI-H tumors (AACR 2025) - "In vivo, oral administration of low daily doses of SNV5686 potently depletes WRN and induces p21 in tumors and leads to deep tumor regression in an MSI-H colorectal xenograft model.Irreversible WRN inhibitors and the non-covalent inhibitor HRO761 leverage binding to CYS727 in the active site to attain potency and selectivity, and published data show that mutation of CYS727 severely abrogates their activity. Furthermore, toxicology studies with SNV5686 have not revealed adverse findings in hematology or clinical chemistry supporting the potential to combine with standard of care agents including chemotherapy. These data support the clinical investigation of SNV5686 for tumors characterized by MSI-H."

MSI-H • Microsatellite Instability • Oncology • CDKN1A • EGFR • MSI • WRN

NTX-452: a non-covalent, potent, selective and highly efficacious WRN inhibitor with best-in-class potential for the treatment of MSI-H tumors (AACR 2025) - "Washout studies using covalent inhibitors revealed that substantial target engagement was lost in MSI-H cells within 24- hours, suggesting rapid WRN resynthesis may limit sustained target inhibition...The preclinical profile of non-covalent NTX-452 was characterized and compared to clinical-stage WRN inhibitors, including those from Novartis (HRO761, non-covalent) and Roche/Vividion (RO7589831, covalent)...Moreover, NTX-452 promoted durable tumor regression and complete responses in MSI-H PDX models that were refractory to immunotherapy (anti-PD1) or chemotherapy. Lastly, resistance to clinical stage WRN inhibitors was explored and the potential for NTX-452 efficacy in WRN inhibitor resistant cell lines and tumors was evaluated.Taken together, our results highlight the broad, best-in-class potential of NTX-452 in MSI-H tumors and support its advancement to clinical evaluation."

MSI-H • Endometrial Cancer • Gastric Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

Comparative analysis of WRN inhibitors HRO761 and VVD-133214 in a cancer cell panel: insights into MSI status-dependent drug responses (AACR 2025) - "Further, transcriptomic profiling elucidated discrete transcriptional landscapes modulated by each inhibitor, shedding light on their divergent pharmacological mechanisms. This study not only showcases our proficiency in high-throughput screening and bioinformatics but also contributes a wealth of knowledge regarding the MSI-dependent therapeutic responses to WRN-targeted agents, potentially informing future clinical strategies in cancer treatment."

Gastric Cancer • Oncology • Solid Tumor • MSI • WRN

YF087 is a potent and selective inhibitor of WRN, specifically targeting MSI-H cancer cells (AACR 2025) - "YF087 is more effective than both WRN reversible inhibitor HRO761 and irreversible inhibitor RG6457 in the SW48 cellular anti-proliferation assay in the presence of 50% human serum. YF087 also possesses favorable preclinical ADME profiles suitable for clinical development. Based on these findings, YF087 is currently in IND-enabling studies to support phase 1 clinical trial in MSI-H/dMMR cancer patients."

IO biomarker • Late-breaking abstract • MSI-H • Tumor mutational burden • Colorectal Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Ovarian Cancer • MSI • TMB • WRN

Novel WRN drug resistant CDX models (AACR 2025) - "The drug resistant tumor tissues were collected after the in vivo drug resistance appeared as regrowth of tumors under 20 mg/kg HRO761 and 5 mg/kg VVD-214 treatment and dissected for primary cell culture to get the drug resistant cell line by escalating drug concentrations in vitro. The WRN inhibitors resistant cell lines were genotype and phenotype checked by STR and IC50 of cell growth when reached the drug resistant index more than 5 times of that of parental cells and indicated that different WRN inhibitors resistant HCT116 cell lines were successfully established and helpful for the discovery of anti-cancer drugs targeted on resistant to WRN inhibitors."

Microsatellite Instability • Oncology • MSI • WRN

Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer. (PubMed, DNA Repair (Amst)) - "Two of these WRN inhibitors, HRO761 and VVD-133214, have recently entered clinical trials. In this review, we summarize recent studies on WRN as a synthetic lethal target in MSI CRC and the development of WRN inhibitors as a new class of anticancer agents."

dMMR • Journal • Mismatch repair • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

Pharmacokinetic Study of HRO761 in Rats by Liquid Chromatography Combined With Electrospray Ionization Tandem Mass Spectrometry. (PubMed, Biomed Chromatogr) - "The oral bioavailability was 79.0%-99.1% over the range of 5-20 mg/kg. This study provides useful information for its further development in clinic."

Journal • PK/PD data • Preclinical

Discovery of novel WRN inhibitors for treating MSI-H colorectal cancers. (PubMed, Bioorg Med Chem Lett) - "In vitro ATPase and cell proliferation assays revealed two candidate chemicals that showed similar or better effects than HRO761. Additionally, an in vivo study demonstrated that KWR095, a newly synthesized WRN inhibitor, has significant anti-proliferative effects compared with vehicle."

Journal • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency. (clinicaltrials.gov) - P1 | N=327 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jan 2030 ➔ May 2029 | Trial primary completion date: Jan 2030 ➔ May 2029

Metastases • Mismatch repair • Trial completion date • Trial primary completion date • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor

Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities. (PubMed, Genome Med) - "Our study thus illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities."

Journal • Oncology • KMT2D • WRN

Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors. (PubMed, Eur J Med Chem) - "The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited...S35 demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors."

Journal • Metabolic Disorders • Microsatellite Instability • Oncology • MSI • WRN

A WRN screening cascade to facilitate novel drug discovery (EORTC-NCI-AACR 2024) - "HRO761 was tested on different cell lines using CTG, including RKO, HCT116, Lovo and SW48 cell line, and in vitro IC50 results showed that these four cell lines were highly sensitive to HRO761, with IC50s of 212.36, 35.64, 291.91, and 71.46 nM, respectively.3) In Vivo Efficacy... WRN helicase is involved in DNA repair pathways, especially in DSB repair. Our WRN screening cascade can provide comprehensive compound evaluation across in vitro and in vivo platforms, thus serve as an efficient screening platform for new drug discovery."

Oncology • WRN

Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers. (PubMed, Nature) - P1 | "These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours."

Journal • Synthetic lethality • Colorectal Cancer • Gastrointestinal Cancer • Metabolic Disorders • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency. (clinicaltrials.gov) - P1 | N=327 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Aug 2026 ➔ Jan 2030 | Trial primary completion date: Aug 2026 ➔ Jan 2030

Metastases • Mismatch repair • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor

Discovery of HRO761, a novel, first-in-class clinical stage WRN inhibitor with potent anti-tumor activity in microsatellite instability high cancers (ACS-Sp 2024) - "Pharmacological inhibition of WRN by HRO761 recapitulates the phenotype observed by WRN genetic suppression, validating WRN as a therapeutic target in MSI high cancers. A phase 1 clinical trial with HRO761 is currently ongoing to assess the safety, tolerability, and preliminary anti-tumor activity in patients with MSI high colorectal cancer and other MSI high solid tumors."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

New target for ’synthetic lethality’! Novartis’ innovative WRN inhibitor receives clinical approval in China [Google translation] (Sina Corp) - "On January 26, the official website of the Center for Drug Evaluation (CDE) of the State Food and Drug Administration of China announced that HRO761, a Class 1 new drug applied by, has received implicit approval for clinical trials and is planned to be developed to treat advanced unresectable or metastatic microsatellite highly incompetent patients. Stable (MSI-H) or mismatch repair deficient solid tumors."

Mismatch repair • New trial • Microsatellite Instability • Oncology • Solid Tumor

A phase I/Ib study of the Werner (WRN) helicase inhibitor HRO761 as single agent and in combination with irinotecan or tislelizumab in patients with microsatellite instability-high (MSIhi) or mismatch repair deficient (dMMR) advanced solid tumors (ESMO 2023) - P1 | "Key eligibility criteria include: 1) Patients with advanced unresectable or metastatic MSIhi or dMMR solid tumors who have progressed after or are intolerant to prior standard therapy; 2) patients should have received at least one prior line of chemotherapy or targeted therapy, and prior immune checkpoint inhibitor therapy (Arm A and C). Checkpoint inhibitor therapy is permitted but not required and prior adjuvant therapy is allowed in Arm B."

Clinical • Combination therapy • Metastases • Mismatch repair • P1 data • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

HRO761, a first-in-class clinical stage WRN inhibitor with potent anti-tumor activity in microsatellite instability high cancers* (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Microsatellite Instability • Oncology • MSI • WRN

HRO761, a first-in-class clinical stage WRN inhibitor with potent anti-tumor activity in microsatellite instability high cancers. (AACR-NCI-EORTC 2023) - No abstract available

Clinical • Microsatellite Instability • Oncology • MSI • WRN

HRO761, a first-in-class, clinical stage WRN inhibitor with potent preclinical anti-tumor activity in MSIhigh models. (AACR-NCI-EORTC 2023) - No abstract available

Preclinical • Oncology • WRN

Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency. (clinicaltrials.gov) - P1 | N=327 | Recruiting | Sponsor: Novartis Pharmaceuticals

New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor