Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors

Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the RAS-...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Nada Tawfeeq, Yonghao Jin, Nazarius S. Lamango
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	PCAIs MAPK KRAS MEK1/2 ERK1/2 p90RSK Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/05a1a60610a44f6fa90ded99059fe538
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:05a1a60610a44f6fa90ded99059fe538
record_format	dspace
spelling	oai:doaj.org-article:05a1a60610a44f6fa90ded99059fe5382021-11-25T17:03:39ZSynthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors10.3390/cancers132257572072-6694https://doaj.org/article/05a1a60610a44f6fa90ded99059fe5382021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5757https://doaj.org/toc/2072-6694Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the RAS-driven cancers. The current study reports on the optimization of the PCAIs and the determination of their mechanisms of action in KRAS-mutant cancer cells. They display ClogP values ranging from 3.01 to 6.35, suppressing the viabilities of KRAS-mutant MDA-MB-231, A549, MIA PaCa-2, and NCI-H1299 cells in 2D and 3D cultures with EC<sub>50</sub> values of 2.2 to 6.8, 2.2 to 7.6, 2.3 to 6.5 and 5.0 to 14 µM, respectively. When A549 cells were treated with the PCAIs, NSL-YHJ-2-27, for 48 h, no significant difference was observed in the levels of total or phosphorylated B- and C-Raf proteins. However, at 5 µM, it stimulated the phosphorylation of MEK1/2, ERK1/2, and p90RSK by 84%, 59%, and 160%, respectively, relative to controls. A non-farnesylated analog, NSL-YHJ-2-62, did not elicit similar effects. These data reveal that effects on the RAS-MAPK signaling axis most likely contribute to the anticancer effects of the PCAIs, possibly through the proapoptotic isoforms of p90RSK. The PCAIs may thus have the potential to serve the unmet therapeutic needs of patients with aberrant hyperactive G-protein signaling.Nada TawfeeqYonghao JinNazarius S. LamangoMDPI AGarticlePCAIsMAPKKRASMEK1/2ERK1/2p90RSKNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5757, p 5757 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	PCAIs MAPK KRAS MEK1/2 ERK1/2 p90RSK Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	PCAIs MAPK KRAS MEK1/2 ERK1/2 p90RSK Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Nada Tawfeeq Yonghao Jin Nazarius S. Lamango Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors
description	Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the RAS-driven cancers. The current study reports on the optimization of the PCAIs and the determination of their mechanisms of action in KRAS-mutant cancer cells. They display ClogP values ranging from 3.01 to 6.35, suppressing the viabilities of KRAS-mutant MDA-MB-231, A549, MIA PaCa-2, and NCI-H1299 cells in 2D and 3D cultures with EC<sub>50</sub> values of 2.2 to 6.8, 2.2 to 7.6, 2.3 to 6.5 and 5.0 to 14 µM, respectively. When A549 cells were treated with the PCAIs, NSL-YHJ-2-27, for 48 h, no significant difference was observed in the levels of total or phosphorylated B- and C-Raf proteins. However, at 5 µM, it stimulated the phosphorylation of MEK1/2, ERK1/2, and p90RSK by 84%, 59%, and 160%, respectively, relative to controls. A non-farnesylated analog, NSL-YHJ-2-62, did not elicit similar effects. These data reveal that effects on the RAS-MAPK signaling axis most likely contribute to the anticancer effects of the PCAIs, possibly through the proapoptotic isoforms of p90RSK. The PCAIs may thus have the potential to serve the unmet therapeutic needs of patients with aberrant hyperactive G-protein signaling.
format	article
author	Nada Tawfeeq Yonghao Jin Nazarius S. Lamango
author_facet	Nada Tawfeeq Yonghao Jin Nazarius S. Lamango
author_sort	Nada Tawfeeq
title	Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors
title_short	Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors
title_full	Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors
title_fullStr	Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors
title_full_unstemmed	Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors
title_sort	synthetic optimization and mapk pathway activation anticancer mechanism of polyisoprenylated cysteinyl amide inhibitors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/05a1a60610a44f6fa90ded99059fe538
work_keys_str_mv	AT nadatawfeeq syntheticoptimizationandmapkpathwayactivationanticancermechanismofpolyisoprenylatedcysteinylamideinhibitors AT yonghaojin syntheticoptimizationandmapkpathwayactivationanticancermechanismofpolyisoprenylatedcysteinylamideinhibitors AT nazariusslamango syntheticoptimizationandmapkpathwayactivationanticancermechanismofpolyisoprenylatedcysteinylamideinhibitors
_version_	1718412754639912960

Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors

Ejemplares similares