702675-74-9

3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a serine-threonine kinase that phosphorylates and activates a range of other kinases, including PKB, PKA, and certain isoforms of PKC. BX-795 is a potent, ATP-competitive inhibitor of PDK1 in vitro (IC₅₀ = 11 nM) and in cells (IC₅₀ = 300 nM). At comparable concentrations, BX-795 also inhibits ERK8, MAPK-interacting kinase 2, Aurora B, Aurora C, MAP/microtubule affinity-regulating kinases 1-4, TNF receptor associated factor-associated NF-κB activator-binding kinase 1, IκB kinase ε, and additional kinases.

BX795 was initially developed as a PDK1 inhibitor (direct competitive inhibitor IC50 = 11nM for PDK1) and has been shown to be a potent and relatively specific inhibitor of TBK1 and IKK-ε. It blocks the phosphorylation, nuclear translocation, and transcriptional activity of interferon regulatory factor 3. BX795 also is a potent inhibitor of cell growth of multiple cancer cell lines with IC50 values ranging from submicromolar amounts (0.368 μM to greater than 450 μM).

ChEBI: N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide is a member of ureas.

BX-795 competes for the ATP (adenosine triphosphate) binding pocket of 3-phosphoinositide-dependent kinase-1 (PDK1) with its substrate ATP. In vitro assays reveal that BX-795 might inhibit Unc-51 (serine/threonine-protein kinase)-like autophagy activating kinase (ULK1).

This nonselective signal transduction inhibitor and antineoplastic agent (FW = 591.47 g/mol; CAS 702675-74-9; Solubility: 120 mg/mL DMSO; <1 mg/mL Water), systematically named N- (3- (5-iodo-4- (3- (thiophene-2- carboxamido) propylamino) pyrimidin-2-ylamino) phenyl) pyrrolidine-1- carboxamide, targets 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. BX-795 targets TBK1 (IC50 = 6 nM), IKKε (IC50 = 41 nM), PDK-1 (IC50 = 111 nM), and ERK8 (IC50 = 140 nM), but acts more broadly by inhibiting MARK1 (IC50 = 55 nM), MARK2 (IC50 = 53 nM), MARK4 (IC50 = 19 nM), NUAK1 (IC50 = 5 nM), VEGFR (IC50 = 157 nM), MLK1 (IC50 = 50 nM), MLK2 (IC50 = 46 nM), MLK3 (IC50 = 42 nM). BX795 also inhibits the phosphorylation of JNK1/2 and p38α MAPK in MEFs stimulated with IL-1α or TNFα. The effect of BX795 on the activation of JNK1/2 and p38α MAPK does not result from the inhibition of TBK1/IKKε.

Store at -20°C

Feldman et al. (2005) Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1; J. Biol. Chem.?280 19867 Bain et al. (2007) The selectivity of protein kinase inhibitors: a further update; Biochem.? J. 408 297 Clark et al. (2009) Use of the Pharmacological Inhibitor BX795 to Study the Regulation and Physiological Roles of TBK1 and IkB Kinase ε; J.? Biol. Chem.?284 14136 Bai et al. (2015) BX795, a TBK1 inhibitor, exhibits antitumor activity in human oral squamous cell carcinoma through apoptosis induction and mitotic phase arrest; Eur.? J. Pharmacol.?769 287 Choi et al. (2019) A pharmacogenomic analysis using L1000CDS2 identifies BX-795 as a potential anticancer drug for primary pancreatic ductal adenocarcinoma cells; Cancer Lett.?465 82 Scuderi et al. (2021) TBK1 Inhibitor Exerts Antiproliferative Effect on Glioblastoma Multiforme Cells; Oncol.? Res.?28 779 Sutlu et al. (2012) Inhibition of Intracellular Antiviral Defense Mechanisms Augments Lentiviral Transduction of Human Natural Killer Cells: Implications for Gene Therapy; Hum. Gene Ther.?23 1090 Allan et al. (2021) Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing e4x vivo expansion; Mol. Ther. Methods Clin. Dev.?20 559 Chockley et al. (2021) Transient blockade of TBK1/IKKε allows efficient transduction of primary human natural killer cells with vesicular stomatitis virus G-pseudotyped lentiviral vectors; Cytotherapy?23 787 Lingyu et al. (2020) Lentiviral delivery of combinatorial CAR/CRISPRi circuit into human primary T cells is enhanced by TBK1/IKKε complex inhibitor BX795; J. Transl. Med.?18 363