VVD-214 / Roche, Bayer - LARVOL DELTA

Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers. (PubMed, J Med Chem) - "This process underscored the tunability of the vinyl sulfone warhead and its effectiveness in covalent drug discovery. VVD-214 induced tumor regression in MSI-H colorectal cancer models and is being evaluated as a promising therapeutic candidate for MSI-H cancers."

Journal • MSI-H • Colorectal Cancer • Metabolic Disorders • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells. (EACR 2025) - "TTP assays and mutagenesis identified recurrent on-target WRN mutations driving resistance, including G729D, which disrupts WRNi binding, causing broad cross-resistance, and I852F, which selectively confers resistance to HRO761 while preserving sensitivity to VVD-133214...Notably, WRNi-resistant cells remained sensitive to ATR inhibitors and irinotecan, supporting a WRN-specific resistance mechanism. Our study identifies on-target WRN mutations as key drivers of three clinical grade WRNi resistance and highlights strategies to overcome it. Our study identifies on-target WRN mutations as key drivers of three clinical grade WRNi resistance and highlights strategies to overcome it. By characterizing cross-resistance across clinical-grade WRNi, we propose switching inhibitors with different mechanisms of action to restore sensitivity. These findings provide a framework for biomarker-driven patient stratification, resistance monitoring through ctDNA, and combinatorial..."

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

Vividion Therapeutics and Bayer Further Strengthen Oncology Development Pipeline with Clinical-Stage WRN Inhibitor (Bayer Press Release) - "Vividion Therapeutics, Inc...and a wholly owned and independently operated subsidiary of Bayer AG, today announced it has secured exclusive worldwide rights to develop and commercialize the clinical-stage Werner helicase (WRN) covalent inhibitor VVD-214 (RO7589831), strengthening and complementing its innovative oncology development pipeline."

Commercial • MSI-H • Colorectal Adenocarcinoma • Endometrial Cancer • Gastric Cancer • Microsatellite Instability • Ovarian Cancer

Top 5 MD Anderson abstracts at AACR 2025 (MD Anderson Press Release) - "The American Association for Cancer Research (AACR) Annual Meeting showcases exciting new cancer therapies that help link translational science and clinical trials. MD Anderson researchers will be presenting more than 200 studies at AACR this year."

Clinical data • Non Small Cell Lung Cancer • Solid Tumor • Thyroid Gland Carcinoma

Covalent Werner helicase inhibitor shows clinical proof-of-concept in Phase I trial (Medical Xpress) - P1 | N=295 | NCT06004245 | Sponsor: Hoffmann-La Roche | "Initial efficacy was evaluated in 37 patients. Five of these patients, representing multiple cancer types with high MSI or dMMR, had partial responses as determined by radiological imaging, and 65.7% of all patients had lasting stable disease. Specialized metabolic imaging showed that deeper metabolic responses were associated with both radiological partial responses and longer-term disease control. Safety was evaluated in 44 patients, with the majority experiencing grade 1–2 adverse events, though higher doses appeared less tolerable than lower doses. Mild manageable nausea, vomiting and diarrhea were the most common adverse events, and no dose-limiting toxicities were observed."

dMMR • MSI-H • P1 data • Microsatellite Instability • Oncology • Solid Tumor

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

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

First-in-human (FIH) phase 1 trial of the oral first-in-class covalent Werner helicase (WRN) inhibitor RO7589831 in patients with microsatellite instable (MSI) and/or mismatch repair deficient (dMMR) advanced solid tumors (AACR 2025) - P1 | "RO7589831 is generally safe and well tolerated, with promising DCR, durable RECISTv1.1, FDG-PET metabolic and ctDNA molecular responses in pts with advanced MSI cancers, including ICI-treated pts, providing the first early clinical proof-of-concept for effectively drugging WRN. Dose optimization cohorts are ongoing to establish the RP2D."

Clinical • dMMR • Metastases • Mismatch repair • P1 data • Endometrial Cancer • Oncology • Solid Tumor • 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

A Study to Evaluate the Safety, Pharmacokinetics, and Anti-Tumor Activity of RO7589831 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=295 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2027 ➔ May 2027 | Trial primary completion date: Dec 2027 ➔ May 2027

Mismatch repair • Monotherapy • Trial completion date • Trial primary completion date • Microsatellite Instability • Oncology • Solid Tumor • MSI

A Study to Evaluate the Safety, Pharmacokinetics, and Anti-Tumor Activity of RO7589831 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=295 | Recruiting | Sponsor: Hoffmann-La Roche | N=220 ➔ 295

Combination therapy • Enrollment change • Metastases • Mismatch repair • Monotherapy • Microsatellite Instability • Oncology • Solid Tumor • MSI

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

A Study to Evaluate the Safety, Pharmacokinetics, and Anti-Tumor Activity of RO7589831 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=220 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2027

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