17-AAG Inhibitor CAS No. 75747-14-7

Cat. No.	Name	Size	Price
KI0159	17-AAG	25 mg	$330
	17-AAG	100 mg	$670
	17-AAG	200 mg	$1070

Chemical Characteristic

Product Name	17-AAG
Synonyms	KOS-953, Tanespimycin
CAS No.	75747-14-7
Molecular Weight	585.69
Formula	C₃₁H₄₃N₃O₈
Chemical Name	17-demethoxy-17-(2-propenylamino)- [(3R,5R,6S,7R,8E,10R,11R,12Z,14E)-6-Hydroxy-5,11,21-trimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate
Smiles	C(=O)(N)OC1/C(=C/[C@@H]([C@H]([C@H](C[C@@H](CC2=C(C(=O)C=C(NC(=O)/C(=C/C=C\[C@@H]1OC)/C)C2=O)NCC=C)C)OC)O)C)/C
Chemical Structure

Biological activities

17-AAG is a potent Hsp90 inhibitor. The IC50 of 17-AAG is 5 nM for Hsp90 from HER-2-overexpressing cancer cells including BT474, N87, SKOV3 and SKBR3 while that is 39 nM for Hsp90 from other tumour cells such as MCF7, A549, HT29, MDA468, SKMG3, U87, HT1080 and Hs578t. 17-AAG inhibits Hsp90 from normal human primary cells including NDF, RPTEC, HMVEC, HMEC, HUVEC, Hs578Bst and PBMC cells with an average IC50 of 0.9 µM. Incubation of Hsp90 from BT474 breast carcinoma cells with increasing concentrations of 17-AAG inhibits the binding of Hsp90 to biotin-GM with an IC50 of 6 nM, whereas Hsp90 from primary human renal epithelial cells (RPTEC) and normal dermal fibroblasts (NDF) has an IC50 of 600 nM and 400 nM, respectively. ^[1] 17-AAG ameliorates polyglutamine-mediated motor neuron degeneration.^[2] Low concentration of the HSP90 inhibitor 17-AAG eliminates lymphoma cancer stem cells (CSC) by disrupting the transcriptional function of HIF1α, a client protein of HSP90. 17-AAG preferentially induces apoptosis and eliminates the colony formation capacity of mouse lymphoma CSCs and human acute myeloid leukemia (AML) CSCs.^[3] Treatment of cultured ALCL cells with 17-AAG cause cell-cycle arrest and apoptosis, irrespective of ALK expression. At the molecular level, 17-AAG induces degradation of ALK and Akt proteins and dephosphorylates extracellular signal-regulated kinase. 17-AAG degrades the cell-cycle regulatory protein cyclin D1 and its cyclin-dependent kinases, CDK4 and CDK6, but has a differential effect on p27 and p53 proteins.^[4] Treatment with 17-AAG triggeres the B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) conformational change associated with apoptosis, while Bax-deficient cells are resistant to 17-AAG-induced apoptosis.^[5] Administration of 17-AAG markedly ameliorates motor impairments in the SBMA (spinal and bulbar muscular atrophy) transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant AR (androgen receptor).^[2] 17-AAG administration attenuates soleus muscle atrophy, µ-calpain, increases under hindlimb unloading as well as decrease of pFOXO3 in rats.

Protocols

Molecular levels: Purified native Hsp90 protein or cell lysates in lysis buffer (20mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl_{2, 100 mM KCl) are incubated with or without 17-AAG for 30 minutes at 4°C, and then incubated with biotin-GM linked to BioMag streptavidin magnetic beads for 1 hour at 4°C. Tubes are placed on a magnetic rack, and the unbound supernatant removes. The magnetic beads are washed three times in lysis buffer and heated for 5 minutes at 95°C in SDS??AGE sample buffer. Samples are analysed on SDS protein gels, and western blots done using indicated antibodies. Bands in the western blots are quantified using the Bio-rad Fluor-S MultiImager, and the percentage inhibition of binding of Hsp90 to the biotin-GM is calculated. The IC50 reported is the concentration of 17-AAG needed to cause half-maximal inhibition of binding. For in vitro reconstitution, 5µM of purified Hsp90 is combined with 1µM each of Hsp70, Hsp40, p23 and Hop purified proteins.^[1] In vitro: Cells including high-HER-2 breast carcinoma (BT474, SKBR3), stomach carcinoma (N87) and ovarian carcinoma (SKOV3), MCF7 breast carcinoma, MDA468 breast carcinoma, Hs578T breast carcinoma and paired normal epithelium Hs578Bst, A549 lung carcinoma, HT29 colon carcinoma, U87 glioblastoma, SKMG3 glioblastoma are seeded in 96-well plates at 2,000 cells per well in a final culture volume of 100µL for 24 hours before the addition of increasing concentrations of 17-AAG that is incubated for 5 days. Viable cell number is determined. The value of the background absorbance at 490nm (A490) of wells not containing cells is subtracted. Percentage of viable cells = (A490 of 17-AAG treated sample⁄A490 untreated cells) ×100. The IC50 is defined as the concentration that gave rise to 50% viable cell number.^[1] In vivo: Twenty-two young adult male Wistar rats weighing 191.1 ± 3.2 g are randomly assigned to the ground control (C) group, the hindlimb unloading (HUL) group, or the HUL with HSP90 inhibitor 17-AAG (60 mg/kg i.p.) administration (HUL+17-AAG) group. Control animals receive identical volumes of 20% DMSO vehicle. 17-AAG and vehicle are administered 3 hours prior to the start of the experiment. HUL is carried out for 3 days. At the end of the experiment, rats are euthanized, and the muscles are rapidly removed, weighed, and frozen at -85°C for later analysis. Control animals are processed along with the HUL and HUL + 17-AAG animals.}

References

[1] Kamal A, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003, 425(6956): 407-410. [2] Waza M, et al. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med. 2005, 11(10): 1088-1095. [3] Newman B, et al. HSP90 inhibitor 17-AAG selectively eradicates lymphoma stem cells. Cancer Res. 2012, 72(17): 4551-4561. [4] Georgakis GV, et al.The HSP90 inhibitor 17-AAG synergizes with doxorubicin and U0126 in anaplastic large cell lymphoma irrespective of ALK expression. Exp Hematol. 2006, 34(12): 1670-1679. [5] Nimmanapalli R, et al. Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases.Blood. 2003, 102(1): 269-275.

Please click here to fill online order form, and we will make sure to supply you product with detail information. This process usually takes between 24 to 48 hours, depending on products stock avaliability. All inquires and subsequent projects are handled in the strictest confidence and will be backed by a confidentiality agreement if required.