瑞士诺华生物医学研究中心Marta Cortés-Cros等研究人员合作发现，WRN抑制剂HRO761在MSI癌症中具有合成致死性。2024年4月24日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员报告了处于临床阶段的WRN螺旋酶抑制剂HRO761的结构、生化、细胞和药理学特征。HRO761是一种强效、选择性、异构的WRN抑制剂，能与D1和D2螺旋酶结构域的界面结合，将WRN锁定在非活性构象中。HRO761的药理抑制再现了WRN基因抑制所观察到的表型，以p53非依赖的方式导致DNA损伤并选择性地抑制微卫星不稳定（MSI）细胞中肿瘤细胞的生长。

此外，HRO761在MSI细胞中导致WRN降解，而在微卫星稳定细胞中则没有。口服HRO761可在MSI细胞和患者来源的异种移植模型中，产生剂量依赖性体内DNA损伤诱导和肿瘤生长抑制作用。这些发现代表了WRN作为MSI癌症治疗靶点的临床前药理学验证。HRO761（NCT05838768）的临床试验正在进行中，以评估其在MSI结直肠癌和其他MSI实体瘤患者中的安全性、耐受性和初步抗肿瘤活性。

据悉，通过几项基因筛选，沃纳综合征RecQ螺旋酶WRN被确定为MSI癌细胞的合成致死靶点。尽管免疫检查点抑制剂的治疗取得了进展，但治疗MSI癌症的需求仍未得到满足。

附：英文原文

Title: Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

Author: Ferretti, Stephane, Hamon, Jacques, de Kanter, Ruben, Scheufler, Clemens, Andraos-Rey, Rita, Barbe, Stephanie, Bechter, Elisabeth, Blank, Jutta, Bordas, Vincent, Dammassa, Ernesta, Decker, Andrea, Di Nanni, Noemi, Dourdoigne, Marion, Gavioli, Elena, Hattenberger, Marc, Heuser, Alisa, Hemmerlin, Christelle, Hinrichs, Jrgen, Kerr, Grainne, Laborde, Laurent, Jaco, Isabel, Nez, Elosa Jimnez, Martus, Hans-Joerg, Quadt, Cornelia, Reschke, Markus, Romanet, Vincent, Schaeffer, Fanny, Schoepfer, Joseph, Schrapp, Maxime, Strang, Ross, Voshol, Hans, Wartmann, Markus, Welly, Sarah, Zcri, Frdric, Hofmann, Francesco, Mbitz, Henrik, Corts-Cros, Marta

Issue&Volume: 2024-04-24

Abstract: The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1–6. Despite advances in treatment with immune checkpoint inhibitors7–10, there is an unmet need in the treatment of MSI cancers11–14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.

DOI: 10.1038/s41586-024-07350-y

Source: https://www.nature.com/articles/s41586-024-07350-y