Abstract
Abstract Zasocitinib (TAK-279) is an oral, allosteric, highly selective, tyrosine kinase 2 (TYK2) inhibitor in late-stage clinical development for the treatment of immune-mediated inflammatory diseases, including psoriasis. Zasocitinib was developed using AI-assisted compound design strategy to create a TYK2 inhibitor with next-generation selectivity and >1 million-fold greater affinity for TYK2 than for Janus kinase (JAK) 1/2/3. This study compared the potency and selectivity of zasocitinib for TYK2 vs. JAK1/3 with licensed TYK2/JAK inhibitors. The inhibitory constants (Kis) of zasocitinib and deucravacitinib for JAK1 and TYK2 Janus homology 2 (JH2) domains were determined using a homogeneous time-resolved fluorescence assay. Fresh whole-blood cultures from 12 to 13 healthy volunteers characterized concentration–response (percentage inhibition) curves for TYK2- (IL-12/18 IFN-γ) and JAK1/3- (IL-2 pSTAT5) dependent pathways for zasocitinib and licensed TYK2/JAK inhibitors. Statistical modelling determined the relationship between concentration and percentage inhibition, and half-maximal inhibitory concentration (IC50) values were estimated. Drug plasma concentrations at clinically relevant/approved doses were simulated using published population pharmacokinetic models. Time over plasma concentrations >IC50 and percentage daily inhibition were compared between drugs for each pathway. The Kis of zasocitinib and deucravacitinib for the JAK1 JH2 domain were >15 000 and 1 nM, respectively. The Kis of zasocitinib and deucravacitinib for the TYK2 JH2 domain were 0.0087 and 0.0115 nM, respectively. Simulated plasma concentrations were above TYK2 IC50 for 24 h for zasocitinib 30 mg once daily (QD) vs. 3 h for deucravacitinib 6 mg QD, and 0 h for baricitinib 4 mg QD, tofacitinib 10 mg twice daily and upadacitinib 30 mg QD. TYK2 percentage daily inhibition was 91% for zasocitinib 30 mg and 23% for deucravacitinib 6 mg. Baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg showed minimal TYK2 inhibition (0–8%). Simulated plasma concentrations of zasocitinib 30 mg and deucravacitinib 6 mg did not reach JAK1/3 IC50; those of baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg were above JAK1/3 IC50 for 24 h. JAK1/3 percentage daily inhibition was 0% for zasocitinib 30 mg and 3% for deucravacitinib 6 mg vs. 91–97% for baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg. Selective TYK2 inhibition offers a distinct cytokine receptor inhibition profile. Zasocitinib showed greater and longer selective inhibition of TYK2-mediated signalling vs. deucravacitinib at its clinical dosage, without affecting JAK1/3-mediated signalling.
Published Version
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