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作者：SCI天天读
SCI
14 May 2024
Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers
(Nature, IF: 64.80)
Rita Andraos-Rey, Stephanie Barbe, Elisabeth Bechter, Jutta Blank, Vincent Bordas, Ernesta Dammassa, Andrea Decker, Noemi Di Nanni, Marion Dourdoign1, Elena Gavioli, Marc Hattenberger, Alisa Heuser, Christelle Hemmerlin, Jürgen Hinrichs, Grainne Kerr, Laurent Laborde, Isabel Jaco, Eloísa Jiménez Núñez, Hans-Joerg Martus, Cornelia Quadt, Markus Reschke, Vincent Romanet, Fanny Schaeffer, Joseph Schoepfer, Maxime Schrapp, Ross Strang, Hans Voshol, Markus Wartmann, Sarah Welly, Frédéric Zécri, Francesco Hofmann, Henrik Möbitz, Marta Cortés-Cros
CORRESPONDENCE TO: henrik.moebitz@novartis.com; marta.cortes-cros@novartis.com
The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens. Despite advances in treatment with immune checkpoint inhibitors, there is an unmet need in the treatment of MSI cancers. 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.
Werner综合征RecQ解旋酶WRN在数个基因筛查中被确定为具有微卫星不稳定性（MSI）的癌症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MSI癌症的治疗需求仍未得到满足。在这里，我们报道了临床阶段WRN解旋酶抑制剂HRO761的结构、生物化学、细胞和药理学特征，该抑制剂是通过创新的苗头化合物发现法和先导优化策略识别出的。HRO761是一种强效、选择性、空间异构的WRN抑制剂，在D1和D2解旋酶结构域的界面结合，将WRN锁定在非活性构象中。HRO761的药理学抑制概括了WRN基因抑制所观察到的表型，导致DNA损伤和以p53非依赖性的方式选择性抑制MSI细胞中的肿瘤细胞生长。此外，HRO761在MSI细胞中导致WRN降解，但在微卫星稳定细胞中没有发生这种现象。在MSI细胞和患者来源的异种移植物模型中，口服HRO761导致剂量依赖性的体内DNA损伤诱导和肿瘤生长抑制。这些发现事WRN作为MSI癌症治疗靶点的临床前药理学验证。一项使用HRO761（NCT05838768）的临床试验正在进行中，以评估MSI结直肠癌和其他MSI实体瘤患者的应用HRO761的安全性、耐受性和初步抗肿瘤活性。
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