出版编号: LB345

摘要标题： HZ-V055, a highly selective pan-RAS molecular glue demonstrated robust potency in RASMut cancer models

分类：Late-Breaking Research: Experimental and Molecular Therapeutics3

时间：2:00 PM-5:00 PM, April 21, 2024

内容简介：

1. In biochemical assays, HZ-V055 more potently disrupted the complex formation of KrasMut(On) and BRAF in a CypA-dependent manner. Additionally, HZ-V055 exhibits significantly enhanced selectivity between Kras G12C/D/V and wild type Ras.

2. HZ-V055 demonstrated 5-10 folds stronger potency in RasMut-addicted cancer cell lines compared to RMC-6236, the IC50 values ranges from pico-molar to sub-nano molar level.

3. In a single-dose PK/PD study, HZ-V055 demonstrated rapid and sustained intratumorally DUSP6 inhibition.

4. In multiple KrasMut-driven PDAC or CRC CDX models, oral administration of HZ-V055 results in robust tumor regression at lower doses (0.04 mg/kg), demonstrating 25~50 folds of efficacy enhancement than RMC-6236. Meanwhile, HZ-V055 is without DUSP6 inhibition effect in mouse ear skin at efficacious dose.

5. In pre-clinical DMPK study, HZ-V055 demonstrated improved oral bioavailability across species.

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