Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
| Autor: | Eunhye Ju, Injae Shin, Eunhye Jeon, SeongShick Ryu, Wonjeong Cho, Namkyoung Kim, Ji Won Lee, Taebo Sim, Young Hoon Kim |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway Mutant Antineoplastic Agents Drug resistance vemurafenib-resistant Catalysis Article lcsh:Chemistry Inorganic Chemistry Cell Line Tumor medicine melanoma Humans Physical and Theoretical Chemistry Vemurafenib type-II kinase inhibitor lcsh:QH301-705.5 Molecular Biology Protein kinase B neoplasms Spectroscopy Chemistry Melanoma Organic Chemistry General Medicine medicine.disease pan-class BRAF inhibitor Computer Science Applications BRAF class I/II/III mutants lcsh:Biology (General) lcsh:QD1-999 Drug Resistance Neoplasm Apoptosis Mutation Cancer research Skin cancer medicine.drug |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 7 International Journal of Molecular Sciences, Vol 22, Iss 3783, p 3783 (2021) |
| ISSN: | 1422-0067 |
| Popis: | Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. The most frequently occurring class I BRAF V600 mutations are sensitive to vemurafenib whereas class II and class III mutants, non-V600 BRAF mutants are resistant to vemurafenib. Herein we report six pyrimido[4,5-d]pyrimidin-2-one derivatives possessing highly potent anti-proliferative activities on melanoma cells harboring BRAF class I/II/III mutants. Novel and most potent derivative, SIJ1777, possesses not only two-digit nanomolar potency but also 2 to 14-fold enhanced anti-proliferative activities compared with reference compound, GNF-7 against melanoma cells (SK-MEL-2, SK-MEL-28, A375, WM3670, WM3629). Moreover, SIJ1777 substantially inhibits the activation of MEK, ERK, and AKT and remarkably induces apoptosis and significantly blocks migration, invasion, and anchorage-independent growth of melanoma cells harboring BRAF class I/II/II mutations while both vemurafenib and PLX8394 have little to no effects on melanoma cells expressing BRAF class II/III mutations. Taken together, our six GNF-7 derivatives exhibit highly potent activities against melanoma cells harboring class I/II/III BRAF mutations compared with vemurafenib as well as PLX8394. |
| Databáze: | OpenAIRE |
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