Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy.

发现具有有利的药代动力学特征和体内抗癌功效的 CDC42 抑制剂。

• 影响指数: 8.039
• 发表时间: 2024 Jun 27
• 来源期刊: J Med Chem
• DOI: 10.1021/acs.jmedchem.4c00855
• PMID: 38866385
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 医学
• 作者列表: Brindani N,Vuong LM,La Serra MA,Salvador N,Menichetti A,Acquistapace IM,Ortega JA,Veronesi M,Bertozzi SM,Summa M,Girotto S,Bertorelli R,Armirotti A,Ganesan AK,De Vivo M

Mesh: Animals; Antineoplastic Agents / pharmacokinetics pharmacology chemistry; Humans; Mice; cdc42 GTP-Binding Protein / antagonists & inhibitors metabolism; Cell Line, Tumor; Drug Discovery; Structure-Activity Relationship; Xenograft Model Antitumor Assays; Pyrimidines / pharmacokinetics chemistry pharmacology chemical synthesis; Female

Abstract

We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.

摘要

我们以前报道了三取代嘧啶先导化合物，即,ARN22089和ARN25062阻断CDC42与其特定下游效应物之间的相互作用，PAK蛋白。这种相互作用对于多种肿瘤类型的进展至关重要。此类抑制剂在体内显示出抗癌功效。这里,我们描述了具有良好药物样特性的第二类CDC42抑制剂。在这里报道的25种化合物中，化合物15（ARN25499）是最佳的先导化合物，具有改善的药代动力学特征，增加生物利用度，和在体内PDX肿瘤小鼠模型中的功效。我们的结果表明，这些CDC42抑制剂代表了发现抗癌药物的一个有前途的化学类别，ARN25499作为临床前开发的额外先导候选物。