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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| Format: | Article |
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/7/3783 |
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| author | Namkyoung Kim Injae Shin Jiwon Lee Eunhye Jeon Younghoon Kim Seongshick Ryu Eunhye Ju Wonjeong Cho Taebo Sim |
| author_facet | Namkyoung Kim Injae Shin Jiwon Lee Eunhye Jeon Younghoon Kim Seongshick Ryu Eunhye Ju Wonjeong Cho Taebo Sim |
| author_sort | Namkyoung Kim |
| collection | DOAJ |
| 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-<i>d</i>]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. |
| first_indexed | 2024-03-10T12:34:24Z |
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| id | doaj.art-00825ae3172043629bb73af20bf574a5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:34:24Z |
| publishDate | 2021-04-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-00825ae3172043629bb73af20bf574a52023-11-21T14:21:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01227378310.3390/ijms22073783Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug ResistanceNamkyoung Kim0Injae Shin1Jiwon Lee2Eunhye Jeon3Younghoon Kim4Seongshick Ryu5Eunhye Ju6Wonjeong Cho7Taebo Sim8KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, KoreaSeverance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, KoreaKU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, KoreaMelanoma 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-<i>d</i>]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.https://www.mdpi.com/1422-0067/22/7/3783melanomavemurafenib-resistantBRAF class I/II/III mutantspan-class BRAF inhibitortype-II kinase inhibitor |
| spellingShingle | Namkyoung Kim Injae Shin Jiwon Lee Eunhye Jeon Younghoon Kim Seongshick Ryu Eunhye Ju Wonjeong Cho Taebo Sim Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance International Journal of Molecular Sciences melanoma vemurafenib-resistant BRAF class I/II/III mutants pan-class BRAF inhibitor type-II kinase inhibitor |
| 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 | melanoma vemurafenib-resistant BRAF class I/II/III mutants pan-class BRAF inhibitor type-II kinase inhibitor |
| url | https://www.mdpi.com/1422-0067/22/7/3783 |
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