1. Design, Synthesis, In Vitro and In Vivo Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of Cancer
- Author
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Brindani, Nicoletta, Vuong, Linh M, Acquistapace, Isabella Maria, La Serra, Maria Antonietta, Ortega, José Antonio, Veronesi, Marina, Bertozzi, Sine Mandrup, Summa, Maria, Girotto, Stefania, Bertorelli, Rosalia, Armirotti, Andrea, Ganesan, Anand K, and De Vivo, Marco
- Subjects
Biomedical and Clinical Sciences ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Oncology and Carcinogenesis ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Humans ,Mice ,Cell Line ,Tumor ,Neoplasms ,Neovascularization ,Pathologic ,p21-Activated Kinases ,Protein Binding ,rho GTP-Binding Proteins ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
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.
- Published
- 2023