Novartis' Oral WRN Helicase Inhibitor HRO761 Targets MSI-High and dMMR Tumors

Key Insights

• Novartis is developing HRO761, an oral allosteric WRN helicase inhibitor, for treating MSI-high and dMMR tumors.
• The discovery of HRO761 emphasized the importance of assay selection and medicinal chemistry strategies for permeability and solubility optimization.
• HRO761's preclinical activity and clinical status are under investigation, with its X-ray structure differentiating it from Vividion's VVD-214.

Novartis is advancing HRO761, an orally available allosteric inhibitor targeting WRN helicase, as a potential treatment for tumors characterized by microsatellite instability-high (MSI-high) and mismatch repair deficiency (dMMR). The development of HRO761 underscores the critical role of selecting appropriate assays during early high-throughput screening (HTS) and employing transferable medicinal chemistry strategies to enhance permeability and solubility. These strategies involve modulating LipE, neutral TPSA, chameleonicity, and non-classical zwitterions.

The optimization process focused on improving drug-like properties to ensure effective oral bioavailability and target engagement. The X-ray structure of HRO761 bound to WRN provides insights into its mechanism of action and how it differentiates from other WRN inhibitors, such as Vividion's VVD-214. Preclinical studies have demonstrated promising activity, warranting further investigation into its clinical potential.

Further research is ongoing to fully characterize HRO761's clinical profile, including its efficacy and safety in patients with MSI-high and dMMR tumors. The chemical synthesis and detailed pharmacological properties of HRO761 are also being explored to support its development as a targeted therapy.