Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine kinase belonging to the Janus kinase (JAK) family. Specifically, the mammalian JAK family has four members: JAK1, JAK2, JAK3, and Tyk2. JAK family members regulate cytokine activated signal transduction by phosphorylating receptors. Specifically, this leads to the recruitment and phosphorylation of signal transducers and the activation of transcription (STAT) proteins. So it affects JAK stat dependent transcription and functional responses.

Tyk2 mainly plays a role in the signal transduction of IL-12 and I-IFN. For Tyk2 specific Tyk2 STAT signaling, the cytokines involved include IL-12 and IL-23 containing P40 and IFN α type I. Moreover, targeting these cytokines with biological agents to interfere with the Tyk2 STAT signaling pathway has been proved to be a feasible treatment for autoimmune and inflammatory diseases. Here, we will introduce a selective and orally active Tyk2 inhibitor, BMS-986202.

BMS-986202 is an Orally Active Tyk2 Inhibitor that Binds to Tyk2 JH2.

At first, BMS-986202 is a potent Tyk2 inhibitor that binds to Tyk2 JH2 with an IC₅₀ of 0.19 nM and a K_i of 0.02 nM. Furthermore, BMS-986202 is remarkably selective over other kinases including Jak family members. Meanwhile, BMS-986202 is also a weak inhibitor of CYP2C19 with an IC₅₀ of 14 μM. Nonetheless, BMS-986202 can be used for IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus research.

Secondly, BMS-986202 inhibits IFNα and IL-23 in Kit225 T cells with IC₅₀ values of 10 nM and 12 nM, respectively. Interestingly, BMS-986202 is potent in the IFNα stimulated STAT5 phosphorylation human whole blood (hWB) assay and mWB with IC₅₀ values of 58 nM and 481 nM, respectively.

Thirdly, BMS-986202 with 3-30 mg/kg/day by p.o. for 9 days inhibits IL-23-driven acanthosis in mice. Importantly, BMS-986202 treatment inhibits IL-12/IL-18-induced IFNγ production in mice. Particularly, BMS-986202 dose-dependently inhibits IFNγ production by 46% and 80% at doses of 2 mg/kg and 10 mg/kg, respectively. Obviously, BMS-986202 is stable in liver microsomes, with half-lives of greater than 120 min in mice, rats, monkeys, and humans and 89 min in dogs. Additionally, the serum protein binding for BMS-986202 in these species ranges from 89.3% to 96.0%, leaving a good range of a free fraction of drug available. BMS-986202 shows oral bioavailability up to 62-100%.

Finally, BMS-986202 is a potent, selective, and orally active Tyk2 inhibitor that binds to Tyk2 JH2.

References:

Chunjian Liu, et al. J Med Chem. 2021 Jan 14;64(1):677-694.