The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homolog IKKε plays an important role in cellular pathways. And, as we all know, these kinases belong to the nuclear factor κB family.
In this article, we will introduce a highly potent, orally active and selective ATP-competitive dual inhibitor of TBK1 and IKKε, BAY-985.
Bay-985 has exhibits different IC50 values (2/30 nM) at low or high ATP concentrations of TBK1.
Firstly, in ACHN and SK-MEL-2 cell lines, In a cell proliferation assay, BAY-985 is active in the cellular mechanistic assay and shows anti-proliferative activity in a few cancer cell lines. It shows IC50s of 900 and 7260 nM for SK-MEL2 (NRAS and TP53 mutated) and ACHN (CDKN2A mutated) cells, respectively.
Nextly, In TR-FRET-based kinase activity inhibition assays using recombinant human enzymes and suitable biotinylated-peptides as substrates. BAY-985 inhibits FLT3, RSK4, DRAK1, and ULK1 with IC50s of 123, 276, 311, and 7930 nM, respectively.
Additionally, in pIRF3 cell-based mechanistic assay.BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 (IRF3) with an IC50 of 74 nM in MDA-MB231 mIRF3 cells.
Lastly, in vivo, In a PK study, BAY-985 exhibits the following parameter values: Liver blood flow: 4.2 L/h/kg, specific liver weight: 43 g/kg body weight; Microsomal protein content 40 mg/g in SD rats.
In female NMRI nude mice bearing SK-MEL-2 human melanoma xenograft model. BAY-985 applies with a dose of 200 mg/kg by oral administration for 111 days.
The compound treatment is well tolerated and the maximum bodyweight loss of less than 10%. However, BAY-985 treatment results in weak antitumor efficacy with a T/Ctumor weight ratio of 0.6.
In conclusion, BAY-985 is a TBK1 (TANK-binding kinase 1) and its homolog IKKε inhibitor. BAY-985 can inhibit the cellular phosphorylation of interferon regulatory factor 3. Additionally, it displays antiproliferative efficacy in the melanoma cell line SK-MEL-2 with low IC50 values. However, BAY-985 exhibits only weak antitumor activity in the SK-MEL-2 human melanoma xenograft model.
Reference:
Lefranc J, et al. J Med Chem. 2020 Jan 10.