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. 2025 Dec 25;68(24):25912-25938.
doi: 10.1021/acs.jmedchem.5c01805. Epub 2025 Sep 18.

Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers

Shota Kikuchi  1 , Jason C Green  1 , Don C Rogness  1 , Betty Lam  1 , Zachary A Owyang  1 , Robert D Malmstrom  1 , Ali Tabatabaei  1 , Aaron N Snead  1 , Melissa A Hoffman  1 , Steffen M Bernard  1 , Paige Ashby  1 , Kelsey N Lamb  1 , Benjamin D Horning  1 , Kristen A Baltgalvis  1 , Kent T Symons  1 , Thomas A Glaza  1 , Chu-Chiao Wu  1 , Xiaodan Song  1 , Martha K Pastuszka  1 , John J Sigler  1 , Jonathan Pollock  1 , Laurence Burgess  1 , Gabriel M Simon  1 , Matthew P Patricelli  1 , David S Weinstein  1
Affiliations

Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers

Shota Kikuchi et al. J Med Chem. .

Abstract

Werner syndrome helicase (WRN) has emerged as a compelling therapeutic target for microsatellite instability-high (MSI-H) cancers, owing to its selective dependency on the helicase activity of WRN. Despite the inherent challenges in targeting helicases, our chemoproteomics approach enabled the identification of compounds that covalently engage C727 within an allosteric pocket of WRN, thereby inhibiting its ability to unwind DNA. Through optimization of each molecular component, particularly focusing on the vinyl sulfone warhead and C2 substitution at the pyrimidine core, an optimal balance of intrinsic reactivity, inhibitory potency, and metabolic stability was achieved, culminating in the identification of VVD-214/RO7589831. 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.

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Figures

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1
Structure of VVD-214 (left) and HRO761 (right).
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(a) Dihedral scan performed for the C–C bond to the amide group of 2a and 3a–f without vinyl sulfone (corresponding methyl amide) using AMBER:EHT force field-based torsion scan as implemented in Molecular Operating Environment (MOE, Chemical Computing Group, Montreal, Canada). Preferred orientation of the warhead for (b) 2a and 3a–b (ZCH) and (c) 3c–e (ZN).
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PK/TE of compound 5d via acute subcutaneous administration in HCT116 xenograft mice (female, n = 4). Data shown as means with SEM.
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Antitumor efficacy of compound 5d via subcutaneous administration in HCT116 xenograft mouse model (female, n = 5 for 10 and 30 mg/kg, n = 10 for 100 mg/kg). Data shown as means with SEM and analyzed by one-way ANOVA, **P < 0.01, ****P < 0.0001.
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Tumor TE on WRN C727 at 24 h (tumor TE24h) post single oral dose of compounds 7b, 7d, and VVD-214 in HCT116 xenograft mice (female, n = 3 for 7b, 7d, and n = 4 for VVD-214). Data shown as means with SEM.
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(a) Tumor TE on WRN C727 at 24 h (tumor TE24h) after the last dose of VVD-214 once-daily oral treatment for 3 days in HCT116 xenograft mice (female, n = 4). Data shown as means with SEM (b) TGI (%) vs Tumor TE24h for compound 5d (TE24h measured after single SC dose of 100, 30, and 10 mg/kg) and VVD-214 (TE24h measured after 3 day once-daily PO treatment of 20, 10, and 5 mg/kg).
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MS-based proteomic cysteine profiling for (a) compound 1f at 50 μM and (b) VVD-214 at 2 μM.
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1. Synthesis of VVD-214
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2. Synthesis of the Vinyl Sulfone Warhead
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3. Synthesis of Benzamide Analogs
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4. Synthesis of Pyrimidine Analogs (Except for Pyrimidines 6a, 6d, and 7d)
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5. Synthesis of Pyrimidines 6a, 6d, and 7d
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6. Synthesis of Pyridazine 3e
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