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Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance

Authors
 Namkyoung Kim  ;  Injae Shin  ;  Jiwon Lee  ;  Eunhye Jeon  ;  Younghoon Kim  ;  Seongshick Ryu  ;  Eunhye Ju  ;  Wonjeong Cho  ;  Taebo Sim 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol.22(7) : 3783, 2021-04 
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN
 1661-6596 
Issue Date
2021-04
MeSH
Antineoplastic Agents / chemical synthesis ; Antineoplastic Agents / chemistry ; Antineoplastic Agents / pharmacology* ; Cell Line, Tumor ; Drug Resistance, Neoplasm / drug effects* ; Humans ; Melanoma* / drug therapy ; Melanoma* / genetics ; Melanoma* / metabolism ; Melanoma* / pathology ; Mutation* ; Proto-Oncogene Proteins B-raf* / antagonists & inhibitors ; Proto-Oncogene Proteins B-raf* / genetics ; Proto-Oncogene Proteins B-raf* / metabolism
Keywords
BRAF class I/II/III mutants ; melanoma ; pan-class BRAF inhibitor ; type-II kinase inhibitor ; vemurafenib-resistant
Abstract
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.
Files in This Item:
T202102726.pdf Download
DOI
10.3390/ijms22073783
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Sim, Taebo(심태보)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/184275
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