RU-SKI 43 - CAS 1043797-53-0
Catalog number: 1043797-53-0
Category: Inhibitor
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Molecular Formula:
C22H30N2O2S
Molecular Weight:
386.55
COA:
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Targets:
Hedgehog
Description:
RU-SKI 43 is a small molecule inhibitor of Hhat(Hedgehog acyltransferase), the enzyme responsible for the attachment of palmitate onto Shh.
Purity:
>98%
Synonyms:
RU-SKI 43; RU SKI 43; RUSKI43
MSDS:
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InChIKey:
AEENEMOEBJOKGN-UHFFFAOYSA-N
InChI:
InChI=1S/C22H30N2O2S/c1-4-16(2)13-23-14-22(25)24-10-8-21-19(9-11-27-21)20(24)15-26-18-7-5-6-17(3)12-18/h5-7,9,11-12,16,20,23H,4,8,10,13-15H2,1-3H3
Canonical SMILES:
CCC(C)CNCC(=O)N1CCC2=C(C1COC3=CC=CC(=C3)C)C=CS2
1.Hedgehog acyltransferase as a target in pancreatic ductal adenocarcinoma.
Petrova E;Matevossian A;Resh MD Oncogene. 2015 Jan 8;34(2):263-8. doi: 10.1038/onc.2013.575. Epub 2014 Jan 27.
Sonic Hedgehog (Shh) is abnormally expressed in pancreatic cancer and is associated with disease onset and progression. Inhibition of Shh signaling is thus an attractive clinical target for therapeutic intervention. Most efforts to block Shh signaling have focused on inhibitors of Smoothened, which target the canonical Shh signaling pathway. These approaches have met with limited success, in part due to development of resistance-conferring mutations and contributions from non-canonical signaling pathways. Here, we show that Hedgehog acyltransferase (Hhat), the enzyme responsible for the attachment of palmitate onto Shh, is a novel target for inhibition of Shh signaling in pancreatic cancer cells. Depletion of Hhat with lentivirally delivered small hairpin RNA decreased both anchorage-dependent and independent proliferation of human pancreatic cancer cells. In vivo, Hhat knockdown led to reduction of tumor growth in a mouse xenograft model of pancreatic cancer. RU-SKI 43, a small molecule inhibitor of Hhat recently developed by our group, reduced pancreatic cancer cell proliferation and Gli-1 activation through Smoothened-independent non-canonical signaling. In addition, RU-SKI 43 treatment inhibited two key proliferative pathways regulated by Akt and mTOR.
2.Hedgehog Acyltransferase as a target in estrogen receptor positive, HER2 amplified, and tamoxifen resistant breast cancer cells.
Matevossian A;Resh MD Mol Cancer. 2015 Apr 1;14:72. doi: 10.1186/s12943-015-0345-x.
BACKGROUND: ;Hedgehog acyltransferase (Hhat) catalyzes the transfer of the fatty acid palmitate onto Sonic Hedgehog (Shh), a modification that is essential for Shh signaling activity. The Shh signaling pathway has been implicated in the progression of breast cancer.;METHODS: ;To determine the functional significance of Hhat expression in breast cancer, we used a panel of breast cancer cell lines that included estrogen receptor (ER) positive, HER2 amplified, triple negative, and tamoxifen resistant cells. We monitored both anchorage dependent and independent proliferation of these cells following depletion of Hhat with lentiviral shRNA and inhibition of Hhat activity with RU-SKI 43, a small molecule inhibitor of Hhat.;RESULTS: ;Depletion of Hhat decreased anchorage-dependent and anchorage-independent proliferation of ER positive, but not triple negative, breast cancer cells. Treatment with RU-SKI 43 also reduced ER positive cell proliferation, whereas a structurally related, inactive compound had no effect. Overexpression of Hhat in ER positive cells not only rescued the growth defect in the presence of RU-SKI 43 but also resulted in increased cell proliferation in the absence of drug.
3.Characterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells.
Rodgers UR;Lanyon-Hogg T;Masumoto N;Ritzefeld M;Burke R;Blagg J;Magee AI;Tate EW ACS Chem Biol. 2016 Dec 16;11(12):3256-3262. Epub 2016 Oct 25.
The Sonic Hedgehog (Shh) signaling pathway plays a critical role during embryonic development and cancer progression. N-terminal palmitoylation of Shh by Hedgehog acyltransferase (Hhat) is essential for efficient signaling, raising interest in Hhat as a novel drug target. A recently identified series of dihydrothienopyridines has been proposed to function via this mode of action; however, the lead compound in this series (RUSKI-43) was subsequently shown to possess cytotoxic activity unrelated to canonical Shh signaling. To identify a selective chemical probe for cellular studies, we profiled three RUSKI compounds in orthogonal cell-based assays. We found that RUSKI-43 exhibits off-target cytotoxicity, masking its effect on Hhat-dependent signaling, hence results obtained with this compound in cells should be treated with caution. In contrast, RUSKI-201 showed no off-target cytotoxicity, and quantitative whole-proteome palmitoylation profiling with a bioorthogonal alkyne-palmitate reporter demonstrated specific inhibition of Hhat in cells. RUSKI-201 is the first selective Hhat chemical probe in cells and should be used in future studies of Hhat catalytic function.
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CAS 1043797-53-0 RU-SKI 43

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