Yonsei University College of Medicine discovers ’17a’, a leading substance that inhibits FGFR mutations that cause drug resistance
The target anticancer drug leader 17a effectively inhibits the growth of metastatic, undifferentiated endometrial cancer cells and multiple myeloma cells harboring FGFR mutants. Provided by Yonsei University Medical School
A new target anticancer drug leader that can effectively inhibit mutant receptors that cause various cancers, such as endometrial cancer, multiple myeloma, and bladder cancer, has been derived.
It is expected that new drugs that can solve existing drug resistance can be developed with this lead substance extraction.
A 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.
The research results were published in the latest issue of the international academic journal ‘Journal of Medicinal Chemistry, IF 7.446)’.
FGFR protein is a cell membrane receptor that regulates cell growth, invasion, metastasis, survival and differentiation. If mutated, it can be exposed to various cancers.
Representative FGFR mutants include a ‘gatekeeper mutation’ and a ‘molecular brake mutation’. These mutants cause multiple myeloma, endometrial cancer, cholangiocarcinoma, and bladder cancer.
In particular, FGFR mutant cancers tend to show resistance to existing treatments. For this reason, the task was to find new inhibitors that effectively inhibit FGFR mutants and overcome drug resistance in existing treatments.
The research team has derived the lead substance ’17a’, which shows excellent activity against FGFR mutations resistant to the existing treatment Infigratinib, through novel derivative design synthesis and structure-activity research.
The research team analyzed the inhibitory ability of the derived lead material 17a against FGFR mutants through in vitro evaluation and animal efficacy evaluation.
As a result of the analysis, the lead material 17a not only strongly inhibited the FGFR ‘molecular brake mutant’, but also strongly inhibited the ‘gatekeeper mutant’ than the existing targeted anticancer drugs.
It was confirmed that the lead substance 17a induced apoptosis of cancer cells with FGFR mutants 5 times higher than the existing treatment infigratinib, and inhibited metastasis 4.4 to 9 times higher.
Lead substance 17a inhibited the growth of metastatic, undifferentiated endometrial cancer cells and multiple myeloma cells harboring FGFR mutants by 1.4 to 14 times more than conventional inhibitors.
The research team also conducted an in vivo efficacy test of the lead substance 17a in mice. Cells capable of evaluating the effect of FGFR kinase inhibitors were transplanted into a mouse model, and the lead substance 17a was orally administered once a day for 2 weeks.
In the mouse model administered with the lead substance 17a, the inhibition of mass growth was 69.5% at the same dose (30 mpk) without weight loss, showing better results than the result of administering the conventional inhibitor Infigratinib (51%), and showed bio-efficacy.
Professor Shim Tae-bo said, “With this study, we have derived a new lead material that can effectively inhibit FGFR gatekeeper mutants, which are vulnerable to existing FGFR kinase inhibitors. “He said.
Kwon Dae-ik medical journalist dkwon@hankookilbo.com
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