Background/Purpose: Tyrosine Kinase 2 (TYK2) is a signaling protein within the Janus kinase (JAK) family. It plays a crucial role in transmitting signals from pro-inflammatory cytokines like IL-23, IL-12, and Type I IFN, which contribute to Immune Mediated Inflammatory Diseases (IMIDs). Here we report a novel oral TYK2 inhibitor called FZ007-119, unlike traditional kinase inhibitors that target the catalytic domain, which acts through an allosteric mechanism by binding to the pseudokinase Janus homology 2 regulatory domain (JH2) of the TYK2 enzyme. This specific mode of action allows selective inhibition of TYK2 without affecting other kinases. Current preclinical studies indicate that FZ007-119 shows promise as a treatment for IMIDs while avoiding the side effects associated with non-selective JAK inhibitors.

Methods: We employ our AI-driven structure-based drug design tool to discover selective Tyk2 inhibitors. These compounds are characterized for their drug-like properties, potency, selectivity in both enzyme and cell-based assays, DMPK in vitro and in vivo，as well as in mouse models of psoriasis and atopic dermatitis.

Results: FZ007-119 exhibits high potency and specificity for binding to TYK2 JH2 (IC50=0.19nM). It does not show activity against JH1 (protein kinase domain) of JAK1, JAK2, JAK3 and TYK2 (IC50 >10μM) based on HTRF kinase assays. Cell-based assays on human PBMCs demonstrate that FZ007-119 is a potent inhibitor of IFNα stimulated TYK2 dependent signaling ( IC50 = 12.2 nM) and is selective over GM-CSF induced JAK2 dependent signaling (IC50＞30μM) and IL-2 induced JAK1/3 dependent signaling (IC50＞30μM). FZ007-119 exhibits excellent selectivity against a panel of 207 kinases (less than 50% inhibition at 1μM) and a safety panel of 90 targets (less than 50% inhibition at 10μM). FZ007-119 demonstrates dose-dependent inhibition of ear thickness in an IL-23-induced psoriasis mice model (0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg). It also shows strong efficacy in reducing psoriasis clinical score in an imiquimod-induced mice psoriasis model (3 mg/kg, 10 mg/kg and 30 mg/kg). In a DNFB-induced Atopic Dermatitis model, FZ007-119 (1 mg/kg, 3 mg/kg and 10 mg/kg) significantly reduced lesion scores. FZ007-119 has favorable DMPK profiles, with low risk of drug-drug interactions, no significant inhibition of cytochrome P450 isozymes, and limited inhibition of BCRP or p-gp (IC50 >10μM). It is not a substrate for various transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K). In addition, FZ007-119 exhibits remarkable PK properties and has demonstrated good oral bioavailability in rodents and dogs.

Conclusion: Using our AI-driven drug design tools, we rapidly identified a highly potent and selective TYK2 inhibitor, FZ007-119. Preclinical data support the potential of FZ007-119 as a promising candidate for the treatment of IMIDs such as psoriasis and atopic dermatitis, offering an attractive therapeutic approach with improved efficacy and safety compared to non-selective JAK inhibitors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-profiles-of-fz007-119-a-highly-potent-and-selective-tyk2-inhibitor-for-the-treatment-of-immune-mediated-inflammatory-diseases/