Reference Detail

Ref Type Journal Article
PMID (24171924)
Authors Banerjee S, Buhrlage SJ, Huang HT, Deng X, Zhou W, Wang J, Traynor R, Prescott AR, Alessi DR, Gray NS
Title Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1-tumour-suppressor-activated NUAK kinases.
Journal The Biochemical journal
Vol 457
Issue 1
Date 2014 Jan 01
Abstract Text The related NUAK1 and NUAK2 are members of the AMPK (AMP-activated protein kinase) family of protein kinases that are activated by the LKB1 (liver kinase B1) tumour suppressor kinase. Recent work suggests they play important roles in regulating key biological processes including Myc-driven tumorigenesis, senescence, cell adhesion and neuronal polarity. In the present paper we describe the first highly specific protein kinase inhibitors of NUAK kinases namely WZ4003 and HTH-01-015. WZ4003 inhibits both NUAK isoforms (IC50 for NUAK1 is 20 nM and for NUAK2 is 100 nM), whereas HTH-01-015 inhibits only NUAK1 (IC50 is 100 nM). These compounds display extreme selectivity and do not significantly inhibit the activity of 139 other kinases that were tested including ten AMPK family members. In all cell lines tested, WZ4003 and HTH-01-015 inhibit the phosphorylation of the only well-characterized substrate, MYPT1 (myosin phosphate-targeting subunit 1) that is phosphorylated by NUAK1 at Ser(445). We also identify a mutation (A195T) that does not affect basal NUAK1 activity, but renders it ~50-fold resistant to both WZ4003 and HTH-01-015. Consistent with NUAK1 mediating the phosphorylation of MYPT1 we find that in cells overexpressing drug-resistant NUAK1[A195T], but not wild-type NUAK1, phosphorylation of MYPT1 at Ser(445) is no longer suppressed by WZ4003 or HTH-01-015. We also demonstrate that administration of WZ4003 and HTH-01-015 to MEFs (mouse embryonic fibroblasts) significantly inhibits migration in a wound-healing assay to a similar extent as NUAK1-knockout. WZ4003 and HTH-01-015 also inhibit proliferation of MEFs to the same extent as NUAK1 knockout and U2OS cells to the same extent as NUAK1 shRNA knockdown. We find that WZ4003 and HTH-01-015 impaired the invasive potential of U2OS cells in a 3D cell invasion assay to the same extent as NUAK1 knockdown. The results of the present study indicate that WZ4003 and HTH-01-015 will serve as useful chemical probes to delineate the biological roles of the NUAK kinases.


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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
HTH-01-015 HTH-01-015 1 0
WZ4003 WZ4003 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
HTH-01-015 HTH-01-015 selectively inhibits NUAK1, resulting in decreased cell proliferation and migration (PMID: 24171924).
WZ4003 WZ4003 inhibits NUAK1 and NUAK2, resulting in decreased cell proliferation and migration (PMID: 24171924).
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
Unknown unknown osteosarcoma not applicable WZ4003 Preclinical - Cell culture Actionable In a preclinical study, WZ4003 inhibited MYPT1 phosphorylation and reduced invasive behavior and proliferation of an osteosarcoma cell line in culture (PMID: 24171924). 24171924
Unknown unknown osteosarcoma not applicable HTH-01-015 Preclinical - Cell culture Actionable In a preclinical study, HTH-01-015 inhibited MYPT1 phosphorylation, invasive behavior, and proliferation of an osteosarcoma cell line in culture (PMID: 24171924). 24171924