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

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 downstrea...

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Published inJournal of medicinal chemistry Vol. 66; no. 8; pp. 5981 - 6001
Main Authors 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., De Vivo, Marco
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 27.04.2023
Amer Chemical Soc
Subjects
Animals
Cell Line, Tumor
Chemistry, Medicinal
Humans
Life Sciences & Biomedicine
Mice
Neoplasms
Neovascularization, Pathologic
p21-Activated Kinases - metabolism
Pharmacology & Pharmacy
Protein Binding
rho GTP-Binding Proteins
Science & Technology
NMR
PROTEIN
ACCURATE DOCKING
TUMOR
GLIDE
PARAMETERS
IDENTIFICATION
P21-ACTIVATED KINASES
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Summary: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.
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c00276