BX795 | Dual TBK1/IKKε inhibitor – enhances lentiviral transduction efficiency

BX795 (702675-74-9), originally described as a moderately potent inhibitor of PDK1 (IC₅₀ = 111 nM)¹, is, more importantly, a dual inhibitor of TBK1 and IKKε (IC₅₀’s = 6 and 41 nM respectively)².  TBK1 and IKKε regulate the production of Type I interferons during bacterial and viral infection via phosphorylation of the transcription factor IRF3. It also inhibited of MARK, MLK, NUAK, AurB, and ERK8.³ BX795 exhibited antitumor activity in human oral squamous cell carcinoma⁴, pancreatic ductal adenocarcinoma⁵, and Glioblastoma Multiforme⁶. BX795 has been used to enhance lentiviral transduction efficiency in human NK cells^7-9 and human primary T cells¹⁰ for CAR-T cell therapy.

References/Citations:

1. Feldman et al. (2005) Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1; J. Biol. Chem. 280 19867
2. Bain et al. (2007) The selectivity of protein kinase inhibitors: a further update; Biochem.  J. 408 297
3. 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
4. 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
5. 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
6. Scuderi et al. (2021) TBK1 Inhibitor Exerts Antiproliferative Effect on Glioblastoma Multiforme Cells; Oncol.  Res. 28 779
7. 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
8. 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
9. 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
10. 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