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Ref Type Journal Article
PMID (33917428)
Authors Kim N, Shin I, Lee J, Jeon E, Kim Y, Ryu S, Ju E, Cho W, Sim T
Title Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance.
Journal Vol Issue Date Pages Journal Short Title
International journal of molecular sciences 22 7 2021 Apr 06 Int J Mol Sci
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SIJ777 SIJ777 7 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SIJ777 SIJ 777|SIJ-777 BRAF Inhibitor 25 SIJ777 is a small molecule that inhibits BRAF class I, II, and III mutations, resulting in decreased downstream signaling, and potentially leading to increased apoptosis and decreased migration, invasion, and proliferation of tumor cells (PMID: 33917428).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E melanoma sensitive SIJ777 Preclinical - Cell culture Actionable In a preclinical study, SIJ777 inhibited Mek, Erk, and Akt phosphorylation, proliferation, migration, and invasion, and induced apoptosis in melanoma cell lines harboring BRAF V600E in culture (PMID: 33917428). 33917428
BRAF G466V lung non-small cell carcinoma sensitive SIJ777 Preclinical - Cell culture Actionable In a preclinical study, SIJ777 inhibited proliferation of a non-small cell lung cancer cell line harboring BRAF G466V in culture (PMID: 33917428). 33917428
BRAF G464E melanoma sensitive SIJ777 Preclinical - Cell culture Actionable In a preclinical study, SIJ777 inhibited Mek, Erk, and Akt phosphorylation, proliferation, migration, invasion, and colony formation, and induced apoptosis in a melanoma cell line harboring BRAF G464E in culture (PMID: 33917428). 33917428
BRAF G469E melanoma sensitive SIJ777 Preclinical - Cell culture Actionable In a preclinical study, SIJ777 inhibited Mek, Erk, and Akt phosphorylation and proliferation in a melanoma cell line harboring BRAF G469E in culture (PMID: 33917428). 33917428
BRAF G469A lung non-small cell carcinoma sensitive SIJ777 Preclinical - Cell culture Actionable In a preclinical study, SIJ777 inhibited proliferation of a non-small cell lung cancer cell line harboring BRAF G469A in culture (PMID: 33917428). 33917428
BRAF D594G melanoma sensitive SIJ777 Preclinical - Cell culture Actionable In a preclinical study, SIJ777 inhibited Mek, Erk, and Akt phosphorylation, proliferation, migration, and invasion, and induced apoptosis in a melanoma cell line harboring BRAF D594G in culture (PMID: 33917428). 33917428
BRAF G464V triple-receptor negative breast cancer sensitive SIJ777 Preclinical - Cell culture Actionable In a preclinical study, SIJ777 inhibited proliferation of a triple-negative breast cancer cell line harboring BRAF G464V in culture (PMID: 33917428). 33917428