Design, Synthesis, In Vitro and In Vivo Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of Cancer,Journal of Medicinal Chemistry

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Design, Synthesis, In Vitro and In Vivo Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-04-07 , DOI: 10.1021/acs.jmedchem.3c00276
Nicoletta Brindani ₁ , Linh M Vuong ₂ , Isabella Maria Acquistapace ₁ , Maria Antonietta La Serra ₁ , José Antonio Ortega ₁ , Marina Veronesi ₃ , Sine Mandrup Bertozzi ₄ , Maria Summa ₅ , Stefania Girotto ₃ , Rosalia Bertorelli ₅ , Andrea Armirotti ₄ , Anand K Ganesan ₂ , Marco De Vivo ₁

Affiliation

CDC42 GTPases (RHOJ, CDC42, and RHOQ) are overexpressed in multiple tumor types and activate pathways critical for tumor growth, angiogenesis, and metastasis. Recently, we reported the discovery of a novel lead compound, ARN22089, which blocks the interaction of CDC42 GTPases with specific downstream effectors. ARN22089 blocks tumor growth in BRAF mutant mouse melanoma models and patient-derived xenografts (PDXs) in vivo. ARN22089 also inhibits tumor angiogenesis in three-dimensional vascularized microtumor models in vitro. Notably, ARN22089 belongs to a novel class of trisubstituted pyrimidines. Based on these results, we describe an extensive structure–activity relationship of ∼30 compounds centered on ARN22089. We discovered and optimized two novel inhibitors (27, ARN25062, and 28, ARN24928), which are optimal back-up/follow-up leads with favorable drug-like properties and in vivo efficacy in PDX tumors. These findings further demonstrate the potential of this class of CDC42/RHOJ inhibitors for cancer treatment, with lead candidates ready for advanced preclinical studies.

中文翻译：

用于治疗癌症的 CDC42 GTPase 相互作用抑制剂的设计、合成、体外和体内表征

CDC42 GTPases（RHOJ、CDC42 和 RHOQ）在多种肿瘤类型中过度表达，并激活对肿瘤生长、血管生成和转移至关重要的途径。最近，我们报告了一种新型先导化合物 ARN22089 的发现，它可以阻断 CDC42 GTPases 与特定下游效应子的相互作用。ARN22089在体内阻断 BRAF 突变小鼠黑色素瘤模型和患者来源的异种移植物 (PDX) 中的肿瘤生长。ARN22089 还在体外三维血管化微肿瘤模型中抑制肿瘤血管生成。值得注意的是，ARN22089 属于一类新型三取代嘧啶。基于这些结果，我们描述了以 ARN22089 为中心的~30 种化合物的广泛结构-活性关系。我们发现并优化了两种新型抑制剂（27，ARN25062和28，ARN24928），它们是最佳的备用/后续先导化合物，在PDX肿瘤中具有良好的药物样特性和体内疗效。这些发现进一步证明了此类 CDC42/RHOJ 抑制剂用于癌症治疗的潜力，并且主要候选药物已准备好进行高级临床前研究。

更新日期：2023-04-07

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