VVD-214 / Roche, Bayer, Vividion Therapeutics - LARVOL DELTA

A Study to Evaluate the Efficacy of VVD-133214 in Combination With Pembrolizumab Compared With Pembrolizumab Alone in Participants With Advanced Cancer of the Colon or Rectum (clinicaltrials.gov) - P2 | N=140 | Not yet recruiting | Sponsor: Vividion Therapeutics, Inc.

dMMR • Mismatch repair • Monotherapy • New P2 trial • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Microsatellite Instability • Oncology • Rectal Cancer • Solid Tumor • MSI

A Study to Evaluate the Efficacy of VVD-133214 in Combination With Pembrolizumab Compared With Pembrolizumab Alone in Participants With Advanced Cancer of the Colon or Rectum (clinicaltrials.gov) - P2 | N=140 | Recruiting | Sponsor: Vividion Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

dMMR • Enrollment open • Mismatch repair • Monotherapy • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Microsatellite Instability • Oncology • Rectal Cancer • Solid Tumor • MSI

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 • First-in-human • Metastases • Mismatch repair • P1 data • Endometrial Cancer • Oncology • Solid Tumor • MSI • WRN

CRISPR Screening Identifies SMARCAL1 and MRN as Modulators of WRN Dependency in MSI-H Colorectal Cancer. (PubMed, Cancer Res) - "Loss of WRN induces replication stress and double-strand breaks (DSBs), a vulnerability that can be recapitulated by the selective WRN inhibitor HRO761 in MSI cancer cells. Importantly, the key resistance mechanisms identified in this study were independently validated using a structurally distinct clinical-stage WRN inhibitor VVD-214. Collectively, these findings identify the SMARCAL1-MRN-ATM axis as a critical regulator of WRN dependency and provide mechanistic insight into resistance to WRN-targeted therapy."

Journal • MSI-H • Colorectal Cancer • Metabolic Disorders • Microsatellite Instability • Oncology • Solid Tumor • ERCC1 • MSI • MUS81 • RAD50 • WRN

Vividion Therapeutics Doses First Patient in Phase Ib Combination Study of WRN Inhibitor VVD-214 in Patients with Advanced Colorectal Cancer (Businesswire) - "The study is evaluating VVD-214 in combination with bevacizumab in patients with microsatellite instability-high (MSI-high) or deficient mismatch repair (dMMR) colorectal cancer whose disease has progressed following prior lines of therapy....The global Phase Ib clinical trial (NCT06004245) is planned to enroll patients at clinical sites across the U.S., Australia, Belgium, Canada, China, Denmark, France, Malaysia, South Korea, Spain, and the U.K."

dMMR • MSI-H • Trial status • Colorectal Cancer • Microsatellite Instability

WRN under the scalpel: Helicase-domain hotspot & splice-site knock-ins in HCT116 and RKO (AACR 2026) - "Dose-response viability assays (72-96 h, 10-point curves) were fit with four-parameter logistic models to derive IC₅₀; each clone included n≥2-3 biological replicates. This WRN allele panel is immediately deployable to (1) build allele-resolved resistance maps, (2) prioritize chemotype backups based on the C727/I852 complementarity, (3) generate patient-selection/biomarker hypotheses for MSI-H settings, and (4) accelerate SAR and combination strategies—thereby front-loading chemical and clinical derisking for VVD-214- and HRO761-class WRN inhibitors."

Microsatellite Instability • Oncology • MSI • WRN

ETX-880, a potential best-in-class, oral, highly potent and selective covalent inhibitor of Werner helicase for the treatment of microsatellite instability-high (MSI-H) cancers (AACR 2026) - "The preclinical activity of ETX-880 was characterized and compared to clinical stage WRN inhibitors, including RO7589831, HRO761, and GSK4418959 (non-covalent). Importantly, human PK predictions reveal low clearance, high oral bioavailability and long half-life, supporting a low once daily oral efficacious dose. Overall, ETX-880 is a potent, selective, covalent WRN inhibitor with excellent ADMET properties leading to deep and sustained target coverage, highlighting its best-in-class potential in MSI-H cancers."

IO biomarker • MSI-H • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

ZMS-4084, a potent and selective WRN inhibitor induces significant tumor regression and sustained complete responses in MSI-H tumor models (AACR 2026) - "The two clinical-stage WRN inhibitors, HRO761 and RO7589831, have demonstrated the clinical efficacy in phase I trials. In conclusion, we have developed a novel WRN inhibitor, ZMS-4084, which demonstrates robust antitumor activity in both xenograft models and patient-derived organoids representing diverse MSI-H tumor types. Given the synthetic lethality between WRN inhibition and MSI-H status, along with its broad antitumor activity across multiple tumor lineages, ZMS-4084 holds strong potential as a tissue-agnostic therapeutic agent for patients with MSI-H tumors."

IO biomarker • MSI-H • Preclinical • Colorectal Cancer • Microsatellite Instability • Oncology • Ovarian Cancer • Solid Tumor • CDKN1A • MSI • WRN

On-target WRN mutations drive resistance to WRN inhibitors in TA-repeat-expanded MSI cancers (AACR 2026) - "Some WRN mutations conferred broad cross-resistance, whereas others preserved sensitivity to alternative WRNi; for example, I852F retained sensitivity to VVD-133214 but not to HRO761, whereas F730L conferred pan-resistance to both yet remained vulnerable to GSK4418959...Finally, resistant clones remained vulnerable to rational strategies: combining WRNi with irinotecan suppressed resistant outgrowth, while ATR inhibitors and orthogonal WRNi offer additional routes to extend response. These findings establish on-target WRN mutation as the dominant mechanism of resistance to WRN inhibitors and define a framework for resistance-informed clinical trial design. They also outline actionable strategies to detect and overcome resistance, including ctDNA-based molecular monitoring and rational combination therapies to extend clinical benefit."

IO biomarker • Oncology • WRN

Cellular comparison of a covalent and non-covalent WRN inhibitor reveals shared and unique response biomarkers (AACR 2026) - "The WRN inhibitors HRO761 and VVD-214 showed similar response profiles in the tested cancer cell lines, although some differences were observed. This study highlights potential shared and unique response biomarkers for the WRN inhibitors HRO761 and VVD-214."

Biomarker • Microsatellite Instability • Oncology • MLH1 • MSI • WRN

Chemoproteomic-enabled discovery of VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase (AACR 2024) - "There is no abstract associated with this presentation."

Synthetic lethality • Oncology • WRN

Chemoproteomic-enabled discovery of VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase (AACR 2024) - "VVD-214 provided robust tumor regression in multiple MSI-high colorectal cancer cell lines and patient derived xenograft models, including models derived from patients progressing on immune checkpoint therapies. VVD-214 was exceptionally well tolerated, and constitutes a promising oral drug candidate for patients with MSI-high cancers."

Synthetic lethality • Colorectal Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • 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

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 • 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

Discovery and Preclinical Evaluations of Potent, Selective, and Allosteric Covalent WRN Inhibitors with Improved PK Properties. (PubMed, ACS Med Chem Lett) - "It also demonstrated favorable preclinical pharmacokinetic properties with superior plasma stability and exposure compared with VVD-214. Furthermore, compound 22 showed statistically significant antitumor activity in the HCT116 xenograft mouse model with clear dose dependence."

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

Structural insights into WRN helicase reveal conformational states and opportunities for MSI-H cancer drug discovery. (PubMed, Commun Biol) - "Biochemical and biophysical data demonstrate how nucleotide and inhibitor binding remodel these conformations and suggest that known clinical inhibitors (HRO761 and VVD-133214) function by locking WRN in inactive, 'off-DNA' states. Resistance emerged rapidly in vitro, through acquired point mutations as well as altered WRN expression. Together, our findings provide a structural framework for the WRN structural cycle and support the development of next-generation 'on-DNA' inhibitors to overcome resistance."

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

Vividion Publishes Discovery of WRN Inhibitor VVD-214 in Journal of Medicinal Chemistry (Businesswire) - "In the manuscript, researchers report utilizing Vividion’s chemoproteomics platform to identify molecular fragments that covalently bound an allosteric pocket of WRN to lock it into an inactive conformation. These molecules were then optimized through iterative structure-activity relationship testing, with particular focus on the cysteine-reactive electrophile (vinyl sulfone) and the molecule’s core aromatic rings. The resulting structure of VVD-214 was chosen for its balance of potency, selectivity, and drug-like ADME properties. In preclinical studies, VVD-214 was well tolerated and led to robust tumor regression in multiple patient-derived xenograft mouse models of MSI-high colorectal cancer."

MSI-H • Preclinical • Colorectal Cancer • Microsatellite Instability

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