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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
BYS10, a novel selective RET inhibitor, exhibits potent antitumor activity in preclinical models
Fei Qin1, Yiman Chen1, Jinhai Deng1
1Guangzhou Baiyunshan Pharmaceutical Holding Co., Ltd., Baiyunshan Pharmaceutical General Factory/Guangdong Province Key Laboratory for Core Technology of Chemical Raw Materials and Pharmaceutical Formulations, Guangzhou, China.
Background:
Aberrant alterations in the RET gene serve as oncogenic drivers in multiple cancers, making RET kinase inhibition a promising therapeutic strategy. However, acquired resistance limits the clinical efficacy of selective RET inhibitors.
Methods:
Enzymatic assays were used to measure the IC50 of BYS10 against wild-type RET and six mutants/fusions. The anti-RET activity of BYS10 was systematically evaluated through in vitro (cell proliferation inhibition assays) and in vivo (RET-altered xenograft models) experiments. RET phosphorylation inhibition by BYS10 was confirmed via Western blot, and optimized binding for RET G810R/S potent inhibition was verified by molecular docking.
Results:
In enzymatic assays, BYS10 showed low nanomolar potency against wild type RET and six clinically relevant RET mutations/fusions, including RET G810R/S (IC50 0.01-3.47 nM) and RET V804M/L (IC50 2.18-2.65 nM). BYS10 also displayed significant anti-proliferative activity across a panel of RET-altered cell lines, including the inhibition of Ba/F3-KIF5B-RET-G810R/S (IC50 25.94-240.60 nM) and Ba/F3-KIF5B-RET-V804M/L (IC50 13.38-46.09 nM). Supported by favorable pharmacokinetics, BYS10 achieved robust anti-tumor efficacy in diverse RET-driven xenograft models. In Ba/F3-KIF5B-RET xenograft model, BYS10 at 3 mg/kg achieved a TGI% of 78.45%, versus 57.06% for Selpercatinib (P < 0.001). In Ba/F3-KIF5B-RET-V804L xenograft model, BYS10 at 3 mg/kg achieved a TGI% of 94.67%, versus 79.48% for Selpercatinib (P < 0.05). In Ba/F3-KIF5B-RET G810R xenograft model, BYS10 at 10 mg/kg achieved a TGI% of 65.96%, versus 35.37% for Selpercatinib (P < 0.001). In Ba/F3-KIF5B-RET G810S xenograft model, BYS10 at 10 mg/kg achieved a TGI% of 112.59%, versus 82.15% for Selpercatinib (P < 0.001). Western blot analysis confirmed potent suppression of RET phosphorylation by BYS10. Molecular docking analysis confirmed that BYS10 achieves potent inhibition of RET G810R/S proteins through an optimized binding mode.
Conclusion:
Collectively, BYS10 represents a novel, highly selective RET inhibitor with superior in vitro and in vivo activity against multiple RET alterations compared to Selpercatinib. Its recent Investigational New Drug (IND) approvals from the FDA and NMPA underscore its therapeutic potential for RET-driven malignancies.
Insights
BYS10 is a novel RET inhibitor demonstrating potent activity against various RET alterations, outperforming Selpercatinib in preclinical models. Its Investigational New Drug approvals highlight its potential for treating RET-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant RET gene alterations drive multiple cancers.
- RET kinase inhibition is a key therapeutic strategy.
- Acquired resistance limits current RET inhibitor efficacy.
Purpose of the Study:
- To evaluate BYS10 as a novel RET inhibitor.
- To assess BYS10's efficacy against wild-type RET and resistant mutations.
- To compare BYS10's anti-tumor activity with Selpercatinib.
Main Methods:
- Enzymatic assays to determine IC50 values.
- In vitro cell proliferation inhibition assays.
- In vivo xenograft models to evaluate anti-tumor efficacy.
- Western blot and molecular docking for mechanism validation.
Main Results:
- BYS10 exhibited low nanomolar potency against wild-type RET and six RET mutations/fusions.
- Significant anti-proliferative activity was observed in RET-altered cell lines.
- BYS10 demonstrated superior anti-tumor efficacy compared to Selpercatinib in preclinical xenograft models.
- BYS10 confirmed potent RET phosphorylation inhibition and optimized binding to RET G810R/S.
Conclusions:
- BYS10 is a highly selective RET inhibitor with superior in vitro and in vivo activity.
- BYS10 shows significant therapeutic potential for RET-driven malignancies.
- FDA and NMPA Investigational New Drug approvals support BYS10's clinical development.
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