Development of targeted treatment for endometrial cancer and multiple myeloma ‘green light’

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A research team in Korea has discovered a new target anticancer drug leader that can effectively inhibit mutant receptors that cause various cancers, such as multiple myeloma, endometrial cancer, and bladder cancer.

Professor Shim Tae-bo of the Department of Biomedical Sciences, Yonsei University.

The research team led by Professor Shim Tae-bo of the Department of Biomedical Sciences at Yonsei University announced on the 17th that they have discovered a new target anticancer drug leader that effectively inhibits fibroblast growth factor receptor (FGFR) mutants that cause drug resistance.

According to the research team, FGFR protein is a cell membrane receptor that regulates cell growth, invasion, metastasis, survival and differentiation. Representative FGFR mutants include a ‘gatekeeper mutation’ and a ‘molecular brake mutation’. These mutants cause multiple myeloma, endometrial cancer, cholangiocarcinoma, and bladder cancer. Cancers caused by FGFR mutants tend to show resistance to existing treatments.

Through novel derivative design synthesis and structure-activity research, the research team has derived the lead material ’17a’, which shows excellent activity against FGFR mutants resistant to the existing treatment, Infigratinib.

The research team analyzed the inhibitory ability of 17a against FGFR mutants through in vitro evaluation and animal efficacy evaluation.

As a result of the analysis, 17a was found to strongly inhibit molecular break mutations and gatekeeper mutations. In addition, it was confirmed that 17a induced apoptosis about 5 times higher in cancer cells harboring FGFR mutants than infigratinib, and inhibited metastasis up to 9 times.

(Above figure) Metastatic ability of undifferentiated endometrial cancer cells (AN3CA) and bladder cancer cells (J82) to inhibit metastasis.  17a was found to inhibit the growth of metastatic undifferentiated endometrial cancer cells and multiple myeloma cells harboring FGFR mutants 1.8 to 14 times higher than that of conventional inhibitors.  (Figure below) Bioefficacy of 17a using FGFR3-V555M-Ba/F3 implanted mouse model.  The mouse model administered with 17a showed a better result than the result of administration of infigratinib (51%) with 69.5% inhibition of mass growth. (Data provided by Severance)
(Above figure) Metastatic ability of undifferentiated endometrial cancer cells (AN3CA) and bladder cancer cells (J82) to inhibit metastasis. 17a was found to inhibit the growth of metastatic undifferentiated endometrial cancer cells and multiple myeloma cells harboring FGFR mutants 1.8 to 14 times higher than that of conventional inhibitors. (Figure below) Bioefficacy of 17a using FGFR3-V555M-Ba/F3 implanted mouse model. The mouse model administered with 17a showed a better result than the result of administration of infigratinib (51%) with 69.5% inhibition of mass growth. (Data provided by Severance)

17a was also shown to inhibit the growth of metastatic undifferentiated endometrial cancer cells and multiple myeloma cells harboring FGFR mutants up to 14-fold compared to conventional inhibitors.

The research team also conducted a bioefficacy test of the lead material 17a through a mouse experiment. Cells capable of evaluating the effect of FGFR kinase inhibitors were transplanted into a mouse model, and 17a was orally administered once a day for 2 weeks.

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The mouse model administered with 17a showed a better result than the result of administration of infigratinib (51%) with 69.5% inhibition of mass growth at the same dose (30mpk) without weight loss.

Professor Shim said, “Through this study, we have derived a new lead material that can effectively inhibit FGFR gatekeeper mutants. will be,” he said.

Meanwhile, the results of this study were published in the latest issue of ‘Journal of Medicinal Chemistry’, an international scientific journal in the field of pharmaceutical chemistry.

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