HTH-01-015

• CAT Number: I002057
• CAS Number: 1613724-42-7
• Molecular Formula: C26H28N8O
• Molecular Weight: 468.55
• Purity: ≥95%
• Synonyms: 2,7,9-trimethyl-5-[(1-piperidin-4-ylpyrazol-4-yl)amino]-2,4,6,9-tetrazatetracyclo[9.8.0.03,8.013,18]nonadeca-1(19),3,5,7,11,13,15,17-octaen-10-one
• InChI: InChI=1S/C26H28N8O/c1-16-23-24(31-26(29-16)30-19-14-28-34(15-19)20-8-10-27-11-9-20)32(2)22-13-18-7-5-4-6-17(18)12-21(22)25(35)33(23)3/h4-7,12-15,20,27H,8-11H2,1-3H3,(H,29,30,31)
• InChIKey: CHSDJDLAKKAWCI-UHFFFAOYSA-N
• SMILES: CC1=C2C(=NC(=N1)NC3=CN(N=C3)C4CCNCC4)N(C5=CC6=CC=CC=C6C=C5C(=O)N2C)C

HTH-01-015 is a selective NUAK1/ARK5 inhibitor (IC50 is 100 nM). HTH-01-015 inhibits NUAK1 with >100-fold higher potency than NUAK2 (IC50 of >10 μM).
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[1].

Reference

[1]. Banerjee S, et al. 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.
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