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

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Abstract

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 Cmax and AUC0-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.

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Acknowledgements

These authors acknowledge staff members' help from the Hefei Blooming Drug Safety Evaluation Co., Ltd, and Institute of Clinical Pharmacology, Anhui Medical University, in conducting these studies. The authors would like to acknowledge Hongzhang Sun for performing the formulation study and manufacturing work of the test article. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China

    Shengfu Wang, Xiang Wang, Lina Huang, Jiajie Kuai, Wei Wei & Shangxue Yan

  2. Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education; Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, 81 Meishan Road, Hefei, 230032, China

    Shengfu Wang, Xiang Wang, Lina Huang, Jiajie Kuai, Wei Wei & Shangxue Yan

  3. Hefei Blooming Drug Safety Evaluation Co., Ltd, 358 Ganquan Road, Hefei, 230031, China

    Chunyan Wang, Xiao Wang & Xiaorong Lu

  4. Anhui Province Key Laboratory of Druggability Evaluation for New Drugs, 358 Ganquan Road, Hefei, 230031, China

    Chunyan Wang, Xiao Wang & Xiaorong Lu

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  1. Shengfu Wang
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  2. Chunyan Wang
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  4. Xiang Wang
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  8. Xiaorong Lu
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Correspondence to Xiaorong Lu or Shangxue Yan.

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All procedures performed in involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Wang, S., Wang, C., Wang, X. et al. Antitumor efficacy of CHMFL-KIT-110 solid dispersion in mouse xenograft models of human gastrointestinal stromal tumors. Cancer Chemother Pharmacol 88, 795–804 (2021). https://doi.org/10.1007/s00280-021-04332-z

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