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

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 sen...

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Autores principales: Kim, Namkyoung, Shin, Injae, Lee, Jiwon, Jeon, Eunhye, Kim, Younghoon, Ryu, Seongshick, Ju, Eunhye, Cho, Wonjeong, Sim, Taebo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038755/
https://www.ncbi.nlm.nih.gov/pubmed/33917428
http://dx.doi.org/10.3390/ijms22073783
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author Kim, Namkyoung
Shin, Injae
Lee, Jiwon
Jeon, Eunhye
Kim, Younghoon
Ryu, Seongshick
Ju, Eunhye
Cho, Wonjeong
Sim, Taebo
author_facet Kim, Namkyoung
Shin, Injae
Lee, Jiwon
Jeon, Eunhye
Kim, Younghoon
Ryu, Seongshick
Ju, Eunhye
Cho, Wonjeong
Sim, Taebo
author_sort Kim, Namkyoung
collection PubMed
description 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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spelling pubmed-80387552021-04-12 Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance Kim, Namkyoung Shin, Injae Lee, Jiwon Jeon, Eunhye Kim, Younghoon Ryu, Seongshick Ju, Eunhye Cho, Wonjeong Sim, Taebo Int J Mol Sci Article 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. MDPI 2021-04-06 /pmc/articles/PMC8038755/ /pubmed/33917428 http://dx.doi.org/10.3390/ijms22073783 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, Namkyoung
Shin, Injae
Lee, Jiwon
Jeon, Eunhye
Kim, Younghoon
Ryu, Seongshick
Ju, Eunhye
Cho, Wonjeong
Sim, Taebo
Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
title Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
title_full Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
title_fullStr Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
title_full_unstemmed Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
title_short Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
title_sort novel and potent small molecules against melanoma harboring braf class i/ii/iii mutants for overcoming drug resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038755/
https://www.ncbi.nlm.nih.gov/pubmed/33917428
http://dx.doi.org/10.3390/ijms22073783
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