Antitumor efficacy of CHMFL-KIT-110 solid dispersion in mouse xenograft models of human gastrointestinal stromal tumors

• Published in: Cancer chemotherapy and pharmacology 2021-11, Vol.88 (5), p.795-804
• Main Authors: Wang, Shengfu, Wang, Chunyan, Wang, Xiao, Wang, Xiang, Huang, Lina, Kuai, Jiajie, Wei, Wei, Lu, Xiaorong, Yan, Shangxue
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animal models; Animal research; Animals; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antitumor activity; Benzamides - administration & dosage; Benzamides - pharmacokinetics; Benzamides - pharmacology; Bioavailability; c-Kit protein; Cancer Research; Cell culture; Cell Line, Tumor; Dispersion; Enzyme inhibitors; Gastrointestinal cancer; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - pathology; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - pathology; Humans; Injections, Intravenous; Isonicotinic Acids - administration & dosage; Isonicotinic Acids - pharmacokinetics; Isonicotinic Acids - pharmacology; Kinases; Male; Medicine; Medicine & Public Health; Mice; Oncology; Original Article; Pharmacology/Toxicology; Phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-kit - antagonists & inhibitors; Proto-Oncogene Proteins c-kit - blood; Tumors; Weight; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-021-04332-z

Purpose CHMFL-KIT-110, a selective c-KIT kinase inhibitor for gastrointestinal stromal tumors (GISTs), possesses a poorly water-soluble, limiting the further development of the drug. This study was to investigate the antitumor efficacy of CHMFL-KIT-110 and CHMFL-KIT-110 solid dispersion (laboratory code: HYGT-110 SD) in GIST tumor xenograft models and to explore the PK/PD relationship of HYGT-110 SD. Methods Plasma concentrations of HYGT-110 and HYGT-110 SD were determined by LC–MS/MS in KM mice. Antitumor activity was evaluated by measuring tumor volume and weight in c-KIT-dependent GIST xenograft models. PK/PD relationship was assessed by LC–MS/MS and Western Blot in the GIST-T1 xenografted mice. Results HYGT-110 exhibited a low oral bioavailability (10.91%) in KM mice. Compared with HYGT-110 treatment, the C max and AUC 0- t of HYGT-110 SD in mice plasma were substantially increased by 18.81 and 6.76-fold, respectively. HYGT-110 SD (10, 30, and 100 mg/kg/day) also could dose-dependently decrease the tumor volume and weight in the GIST-882 cell-inoculated xenograft mouse models and show 86.35% tumor growth inhibition (TGI) at 28 days at a 25 mg/kg bid dosage in the GIST-T1 cell-inoculated xenograft mouse model. The free concentration of HYGT-110 in plasma was closely correlated with the inhibition of c-KIT phosphorylation levels in tumor tissues. Conclusions In comparison with the HPMC formulation, both improved PK and PD characteristics of the solid dispersion formulation of CHMFL-KIT-110 were observed in in vivo animal experiments.