Reference Detail

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 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 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 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 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 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
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