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<p>GT-14, identified as [(E)-4-((1-(1-methyl-1H-indol-2-yl) ethylidene)amino)phenol], is a novel inhibitor targeting the Gα<sub>i</sub>2 protein, which is crucial in facilitating cell migration and invasion in prostate, ovarian, and breast cancer cells. therefore a valuable target for treating metastatic castration-resistant prostate cancer (mCRPC). In this study, GT-14’s physicochemical properties, permeability, metabolic behavior, and tissue distribution were assessed. The results showed that GT-14 exhibited very slight aqueous&#xa0;solubility at room temperature (0.11 mg/mL) but was soluble in solvents including dimethyl sulfoxide and dimethyl acetamide, and sparingly or slightly soluble in several cosolvents. GT-14 exhibited a distinct pH-dependent solubility profile, being stable across a broad pH range (1.2–7.4) but degrading in strongly basic conditions. It exhibited high permeability (1.3 x 10<sup>-5</sup> cm/s) in Caco-2 cell culture models and therefore identified as a BCS II compound. Hepatic microsomal studies revealed that GT-14 underwent Phase I metabolism, with more than 90% remaining in 60 min incubation in rat liver microsomes. A stable co-solvent formulation was developed to enable intravenous administration for pharmacokinetic studies. Previous pharmacokinetic studies showed that GT-14 exhibited biphasic disposition with a terminal plasma elimination half-life of 268.07 minutes (&gt; 4 hours). Tissue&#xa0;distribution analysis indicated the highest concentration of GT-14&#xa0;in the prostate, followed by the kidneys, lungs, heart, and liver. Our study presents an early-stage preclinical drug development roadmap that integrates modern technologies for efficiency and success, using GT-14 as a model compound. It showed promising characteristics, reinforcing its potential as a new therapeutic agent for mCRPC.</p>

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Preclinical Development of GT-14, a Novel Inhibitor of Gαi2 Protein: Comprehensive Evaluation of Physicochemical, Metabolic Characteristics and Tissue Distribution

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月1日

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  • Mahua Sarkar,
  • Ting Du,
  • Yuan Chen,
  • Yen V. Maroney Lawrence,
  • Jing Ma,
  • Shafiq A. Khan,
  • Adegboyega K. Oyelere,
  • Dong Liang,
  • Song Gao,
  • Huan Xie

摘要

GT-14, identified as [(E)-4-((1-(1-methyl-1H-indol-2-yl) ethylidene)amino)phenol], is a novel inhibitor targeting the Gαi2 protein, which is crucial in facilitating cell migration and invasion in prostate, ovarian, and breast cancer cells. therefore a valuable target for treating metastatic castration-resistant prostate cancer (mCRPC). In this study, GT-14’s physicochemical properties, permeability, metabolic behavior, and tissue distribution were assessed. The results showed that GT-14 exhibited very slight aqueous solubility at room temperature (0.11 mg/mL) but was soluble in solvents including dimethyl sulfoxide and dimethyl acetamide, and sparingly or slightly soluble in several cosolvents. GT-14 exhibited a distinct pH-dependent solubility profile, being stable across a broad pH range (1.2–7.4) but degrading in strongly basic conditions. It exhibited high permeability (1.3 x 10-5 cm/s) in Caco-2 cell culture models and therefore identified as a BCS II compound. Hepatic microsomal studies revealed that GT-14 underwent Phase I metabolism, with more than 90% remaining in 60 min incubation in rat liver microsomes. A stable co-solvent formulation was developed to enable intravenous administration for pharmacokinetic studies. Previous pharmacokinetic studies showed that GT-14 exhibited biphasic disposition with a terminal plasma elimination half-life of 268.07 minutes (> 4 hours). Tissue distribution analysis indicated the highest concentration of GT-14 in the prostate, followed by the kidneys, lungs, heart, and liver. Our study presents an early-stage preclinical drug development roadmap that integrates modern technologies for efficiency and success, using GT-14 as a model compound. It showed promising characteristics, reinforcing its potential as a new therapeutic agent for mCRPC.