Werner syndrome RecQ helicase-IN-1
[CAS# 2869954-34-5]

Identification

• Classification: Biochemical >> Inhibitor >> DNA damage
• Name: Werner syndrome RecQ helicase-IN-1
• Synonyms: HRO761; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-[4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)piperazin-1-yl]-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]acetamide
• Molecular Formula: C₃₁H₃₁ClF₃N₉O₅
• Molecular Weight: 702.08
• CAS Registry Number: 2869954-34-5
• SMILES: CCC1=C(C(=O)N2C(=NC(=N2)C3=CCOCC3)N1CC(=O)NC4=C(C=C(C=C4)C(F)(F)F)Cl)N5CCN(CC5)C(=O)C6=NC=NC(=C6O)C

Properties

• Density: 1.6±0.1 g/cm³ Calc.^*
• Index of refraction: 1.695 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

Werner syndrome RecQ helicase-IN-1, also known as HRO761, is a selective small-molecule inhibitor developed to target the Werner syndrome ATP-dependent helicase (WRN), a DNA helicase and exonuclease that plays a pivotal role in maintaining genomic integrity. WRN belongs to the RecQ helicase family, which is involved in DNA replication, recombination, repair, and telomere maintenance. Loss-of-function mutations in WRN result in Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. However, pharmacological inhibition of WRN is not aimed at treating this syndrome but rather exploits WRN dependency in certain tumor types.

WRN has emerged as a synthetic lethal target in cancers exhibiting high microsatellite instability (MSI-H), which is a molecular hallmark of defects in the DNA mismatch repair (MMR) system. MSI-H tumors accumulate mutations in repetitive DNA sequences and rely on WRN helicase activity to manage DNA secondary structures and maintain genome stability. In the absence of WRN function, MSI-H cells experience catastrophic DNA damage and cell death, a vulnerability that does not significantly affect microsatellite stable (MSS) cells. This selectivity has driven the development of WRN inhibitors as a targeted approach to exploit the genetic liabilities of MSI-H cancers.

Werner syndrome RecQ helicase-IN-1 was developed to selectively bind to the WRN helicase domain, thereby disrupting its catalytic activity. It induces replication stress and double-stranded DNA breaks in MSI-H tumor cells, triggering cell cycle arrest and apoptosis. In preclinical models, this compound demonstrated significant anti-tumor activity against MSI-H colorectal, endometrial, and gastric cancer cell lines. Moreover, treatment with the inhibitor led to dose-dependent reductions in WRN protein levels, suggesting that the compound not only inhibits but also destabilizes the helicase protein.

In vivo studies using xenograft models further validated the potential of WRN inhibition as an anti-cancer strategy. Oral administration of Werner syndrome RecQ helicase-IN-1 suppressed tumor growth in mice implanted with MSI-H tumors, with minimal observed toxicity in normal tissues. These findings supported the therapeutic index of the compound and its specificity toward MSI-H cancers.

Given the strength of these preclinical findings, clinical development has progressed. Werner syndrome RecQ helicase-IN-1 is currently under evaluation in early-phase clinical trials for patients with advanced solid tumors harboring MSI-H biomarkers. The goals of these trials include establishing safety, determining the recommended dose for expansion, and evaluating pharmacokinetics and early signs of efficacy. Enrollment criteria focus on cancers with confirmed MSI-H status and no standard treatment options.

The identification of WRN as a synthetic lethal target has broadened the landscape of precision oncology, offering new opportunities for exploiting tumor-specific vulnerabilities. Werner syndrome RecQ helicase-IN-1 represents a rationally designed therapeutic agent that capitalizes on this vulnerability with the potential to provide meaningful clinical benefit for patients with difficult-to-treat MSI-H malignancies. The ongoing clinical trials are expected to further define the safety profile, tolerability, and anti-tumor activity of this compound, laying the foundation for potential regulatory approval and integration into clinical practice.