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.
Lefranc J, et al. J Med Chem. 2020 Jan 10.