BX795

PDK1 inhibitor CAS# 702675-74-9

BX795

Catalog No. BCC3635----Order now to get a substantial discount!

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Chemical structure

BX795

3D structure

Chemical Properties of BX795

Cas No. 702675-74-9 SDF Download SDF
PubChem ID 10077147 Appearance Powder
Formula C23H26IN7O2S M.Wt 591.48
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (84.54 mM; Need ultrasonic)
Chemical Name N-[3-[[5-iodo-4-[3-(thiophene-2-carbonylamino)propylamino]pyrimidin-2-yl]amino]phenyl]pyrrolidine-1-carboxamide
SMILES C1CCN(C1)C(=O)NC2=CC=CC(=C2)NC3=NC=C(C(=N3)NCCCNC(=O)C4=CC=CS4)I
Standard InChIKey VAVXGGRQQJZYBL-UHFFFAOYSA-N
Standard InChI InChI=1S/C23H26IN7O2S/c24-18-15-27-22(30-20(18)25-9-5-10-26-21(32)19-8-4-13-34-19)28-16-6-3-7-17(14-16)29-23(33)31-11-1-2-12-31/h3-4,6-8,13-15H,1-2,5,9-12H2,(H,26,32)(H,29,33)(H2,25,27,28,30)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of BX795

DescriptionInhibitor of 3-phosphoinositide-dependent kinase 1 (PDPK1). Inhibits Akt phosphorylation at Thr308 in PC3 cells; also inhibits anchorage-independent growth of PC3 and MDA-MB-468 cells. Exhibits activity at other kinases, including TANK-binding kinase 1 (TBK1), Aurora B and IκB kinase ε (IKKε).

BX795 Dilution Calculator

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BX795 Molarity Calculator

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Preparing Stock Solutions of BX795

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.6907 mL 8.4534 mL 16.9067 mL 33.8135 mL 42.2669 mL
5 mM 0.3381 mL 1.6907 mL 3.3813 mL 6.7627 mL 8.4534 mL
10 mM 0.1691 mL 0.8453 mL 1.6907 mL 3.3813 mL 4.2267 mL
50 mM 0.0338 mL 0.1691 mL 0.3381 mL 0.6763 mL 0.8453 mL
100 mM 0.0169 mL 0.0845 mL 0.1691 mL 0.3381 mL 0.4227 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on BX795

BX795, a small molecule with an aminopyrimidine backbone in its chemical structure, is a potent and ATP-competitive inhibitor of 3-phosphoinositide-dependent kinase 1 (PDK1) that binds to the ATP binding pocket of PDK1 and hence potently inhibits the enzymatic activity of PDK1 in a direct kinase assay format with a value of 50% concentration inhibition IC50 of 11 nM. BX795 is also a potent and selectively inhibitor of TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), with values of IC50 of 0.006 μM and 0.041 μM respectively, that blocks the phosphorylation, nuclear translocation and transcriptional activity of interferon regulatory factor 3 as well as the production of interferon-β in macrophages stimulated with poly(I:C) or lipopolysaccharide (LPS).

Reference

Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S, Buckman BO, Lentz D, Ferrer M, Whitlow M, Adler M, Finster S, Chang Z, Arnaiz DO. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74.

Clark K, Plater L, Peggie M, Cohen P. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. J Biol Chem. 2009 May 22;284(21):14136-46.

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References on BX795

Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation.[Pubmed:19307177]

J Biol Chem. 2009 May 22;284(21):14136-46.

TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKepsilon) regulate the production of Type 1 interferons during bacterial and viral infection, but the lack of useful pharmacological inhibitors has hampered progress in identifying additional physiological roles of these protein kinases and how they are regulated. Here we demonstrate that BX795, a potent and relatively specific inhibitor of TBK1 and IKKepsilon, blocked the phosphorylation, nuclear translocation, and transcriptional activity of interferon regulatory factor 3 and, hence, the production of interferon-beta in macrophages stimulated with poly(I:C) or lipopolysaccharide (LPS). In contrast, BX795 had no effect on the canonical NFkappaB signaling pathway. Although BX795 blocked the autophosphorylation of overexpressed TBK1 and IKKepsilon at Ser-172 and, hence, the autoactivation of these protein kinases, it did not inhibit the phosphorylation of endogenous TBK1 and IKKepsilon at Ser-172 in response to LPS, poly(I:C), interleukin-1alpha (IL-1alpha), or tumor necrosis factor alpha and actually enhanced the LPS, poly(I:C), and IL-1alpha-stimulated phosphorylation of this residue. These results demonstrate that the phosphorylation of Ser-172 and the activation of TBK1 and IKKepsilon are catalyzed by a distinct protein kinase(s) in vivo and that TBK1 and IKKepsilon control a feedback loop that limits their activation by LPS, poly(I:C) and IL-1alpha (but not tumor necrosis factor alpha) to prevent the hyperactivation of these enzymes.

BX795, a TBK1 inhibitor, exhibits antitumor activity in human oral squamous cell carcinoma through apoptosis induction and mitotic phase arrest.[Pubmed:26607461]

Eur J Pharmacol. 2015 Dec 15;769:287-96.

TANK-binding kinase 1 (TBK1), a member of IkappaB Kinase (IKK)-related kinases, plays a role in regulating innate immunity, inflammation and oncogenic signaling. This study aims to investigate the role of BX795, an inhibitor of TBK1, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antitumor effects and mechanisms of BX795 were assessed by MTT assays, flow cytometry, Western blotting, and confocal microscopy. BX795 exhibited a dose-responsive antiproliferative effect on OSCC cells with relative sparing of normal human oral keratinocytes. The compound caused apoptosis as evidenced by PARP cleavage, the presence of pyknotic nuclei in the TUNEL assay, and fragmented DNA tails in the Comet assay. BX795 inhibits Akt and NF-kappaB signaling, arrests cells in the mitotic phase, and increases generation of autophagy in oral cancer cells. Interestingly, the antiproliferative activity of BX795 does not correlate with TBK1 protein expression level in OSCC cells. We propose that the TBK1-independet effect is related to mitotic phase arrest. Pleiotropic anticancer activity with relative sparing of normal oral keratinocytes underscores the potential value of BX795 and warrants its further study in oral squamous cell carcinoma therapy.

Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells.[Pubmed:18514190]

Exp Cell Res. 2008 Jul 1;314(11-12):2299-312.

3-phosphoinositide-dependent kinase-1 (PDK1) phosphorylates and activates several kinases in the cAMP-dependent, cGMP-dependent and protein kinase C (AGC) family. Many putative PDK1 substrates have been identified, but have not been analyzed following transient and specific inhibition of PDK1 activity. Here, we demonstrate that a previously characterized PDK1 inhibitor, BX-795, shows biological effects that are not consistent with PDK1 inhibition. Therefore, we describe the creation and characterization of a PDK1 mutant, L159G, which can bind inhibitor analogues containing bulky groups that hinder access to the ATP binding pocket of wild type (WT) kinases. When expressed in PDK1(-/-) ES cells, PDK1 L159G restored phosphorylation of PDK1 targets known to be hypophosphorylated in these cells. Screening of multiple inhibitor analogues showed that 1-NM-PP1 and 3,4-DMB-PP1 optimally inhibited the phosphorylation of PDK1 targets in PDK1(-/-) ES cells expressing PDK1 L159G but not WT PDK1. These compounds confirmed previously assumed PDK1 substrates, but revealed distinct dephosphorylation kinetics. While PDK1 inhibition had little effect on cell growth, it sensitized cells to apoptotic stimuli. Furthermore, PDK1 loss abolished growth of allograft tumors. Taken together we describe a model system that allows for acute and reversible inhibition of PDK1 in cells, to probe biochemical and biological consequences.

Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1.[Pubmed:15772071]

J Biol Chem. 2005 May 20;280(20):19867-74.

The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.

Description

BX795 is a potent and selective inhibitor of PDK1, with an IC50 of 6 nM. BX795 is also a potent and relatively specific inhibitor of TBK1 and IKKɛ, with an IC50 of 6 and 41 nM, respectively. BX795 blocks phosphorylation of S6K1, Akt, PKCδ, and GSK3β, and has lower selectivity over PKA, PKC, c-Kit, GSK3β etc. BX795 modulates autophagy.

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