The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway in cells

Biological & Pharmaceutical Bulletin
H FukazawaYoshimasa Uehara

Abstract

The resorcylic acid lactone hypothemycin has been shown to inactivate protein kinases by binding to a cysteine conserved in 46 protein kinases, including mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK) and platelet-derived growth factor receptor (PDGFR). We assessed the selectivity of hypothemycin in cellular contexts. Hypothemycin normalized the morphology and inhibited anchorage-independent growth of Ki-ras transformed normal rat kidney (NRK) cells with selectivity and potency comparable to or greater than that of the MEK inhibitor U0126. In Ki-ras-transformed and phorbol 12-myristate 13-acetate (PMA)-treated NRK cells, hypothemycin blocked ERK activation but showed a minimal effect on autophosphorylation of protein kinase D1 (PKD1), another kinase containing the conserved cysteine. Hypothemycin potently inhibited PDGFR autophosphorylation and activation of the MEK-ERK pathway in platelet-derived growth factor (PDGF)-treated NRK cells. However, the phosphoinositide-3-kinase (PI3K) pathway was only modestly attenuated. Hypothemycin also inhibited growth factor- and anchorage-independent growth of human cancer cell lines with a constitutively active MEK-ERK pathway. Although hypothemyc...Continue Reading

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Citations

Jan 7, 2015·European Journal of Medicinal Chemistry·Weiyun ShenJinyan Dong
Oct 17, 2018·Frontiers in Chemistry·Ana S C ValdeiraJorge A R Salvador
Oct 13, 2020·Frontiers in Microbiology·Minh-Thu NguyenFriedrich Götz
May 17, 2021·Seminars in Cancer Biology·Rahim UllahLixin Wan
Oct 11, 2013·Journal of Agricultural and Food Chemistry·Liangxiong XuXiaoyi Wei

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