Design, Synthesis, In Vitro and In Vivo Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of
Nicoletta Brindani1, Linh M Vuong2, Isabella Maria Acquistapace1
1Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, Via Morego 30, Genova 16163, Italy.
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.
Insights
New trisubstituted pyrimidine compounds inhibit CDC42/RHOJ GTPases, blocking tumor growth and angiogenesis. Optimized leads demonstrate in vivo efficacy, advancing cancer treatment potential.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- CDC42 GTPases (RHOJ, CDC42, RHOQ) are frequently overexpressed in various cancers.
- These GTPases play crucial roles in tumor progression, including growth, angiogenesis, and metastasis.
Purpose of the Study:
- To explore the structure-activity relationship (SAR) of novel trisubstituted pyrimidine compounds targeting CDC42 GTPases.
- To identify and optimize potent inhibitors as potential anti-cancer therapeutics.
Main Methods:
- Synthesis and evaluation of approximately 30 trisubstituted pyrimidine analogs based on lead compound ARN22089.
- In vitro assessment of anti-angiogenic properties using vascularized microtumor models.
- In vivo efficacy studies in BRAF mutant mouse melanoma models and patient-derived xenografts (PDXs).
Main Results:
- The lead compound ARN22089 demonstrated significant inhibition of tumor growth and angiogenesis.
- Two optimized compounds, ARN25062 (27) and ARN24928 (28), exhibited favorable drug-like properties and potent in vivo anti-tumor activity in PDX models.
- These compounds effectively block CDC42 GTPase interactions with downstream effectors.
Conclusions:
- Trisubstituted pyrimidines represent a promising class of inhibitors targeting CDC42/RHOJ GTPases for cancer therapy.
- Optimized compounds ARN25062 and ARN24928 are advanced lead candidates for further preclinical development.
- This research validates the therapeutic potential of inhibiting CDC42 GTPases in various cancer types.
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