HTH-01-015 is a potent and selective inhibitor of NUAK1 (IC50 = 100 nM) and does not affect the activity of a panel of 139 other kinases, including additional AMPK family members. The administration of HTH-01-015 to MEFs (mouse embryonic fibroblasts) significantly inhibits migration in a wound-healing assay to a similar extent as NUAK1-knockout. 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. HTH-01-015 impaired the invasive potential of U2OS cells in a 3D cell invasion assay to the same extent as NUAK1 knockdown. HTH-01-015 will serve as useful chemical probes to delineate the biological roles of the NUAK kinases.
CAS Number: 1613724-42-7
Molecular Weight: 468.55
Chemical Name: 4,5,13-trimethyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5,13-dihydro-6H-naphtho[2,3-e]pyrimido[5,4-b][1,4]diazepin-6-one
Appearance: Solid Power.
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥360 days if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
HTH-01-015 is a specific NUAK1 inhibitor. 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) tumor suppressor kinase. HTH-01-015 inhibits NUAK1 with an IC50 of 100 nM, but does not significantly inhibit NUAK2 (IC50 of >10 μM). In all cell lines tested, HTH-01-015 inhibits the phosphorylation of the only well-characterized substrate, MYPT1 (myosin phosphate-targeting subunit 1) that is phosphorylated by NUAK1 at Ser445. In U2OS cells, HTH-01-015 suppresses proliferation and phosphorylation of MYPT1 to the same extent as shRNA-mediated NUAK1 knockdown. In mouse embryonic fibroblasts (MEFs), treatment with 10 μM HTH-01-015 suppresses proliferation and phosphorylation of MYPT1 to the same extent as NUAK1-knockout. To test whether NUAK1 inhibition impaired the ability of the invasive U2OS cells to enter a matrix, 3D Matrigel Transwell invasion assays demonstrate that 10 μM HTH-01-015 markedly inhibits the invasiveness of U2OS cells in this assay.
- Banerjee S, Zagórska A, Deak M, Campbell DG, Prescott AR, Alessi DR. Interplaybetween Polo kinase, LKB1-activated NUAK1 kinase, PP1βMYPT1 phosphatase complex and the SCFβTrCP E3 ubiquitin ligase. Biochem J. 2014 Jul 15;461(2):233-45. doi: 1042/BJ20140408. PubMed PMID: 24785407; PubMed Central PMCID: PMC4109838.
- Banerjee S, Buhrlage SJ, Huang HT, Deng X, Zhou W, Wang J, Traynor R, PrescottAR, Alessi DR, Gray NS. Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1-tumour-suppressor-activated NUAK kinases. Biochem J. 2014 Jan 1;457(1):215-25. doi: 10.1042/BJ20131152. PubMed PMID: 24171924; PubMed Central PMCID: PMC3969223.
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