Discovery of selective TYK2 inhibitors: Design, synthesis, in vitro and in silico studies of promising hits with triazolopyrimidinone scaffold.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway mediates many cytokine and growth factor signals. Tyrosine kinase 2 (TYK2), one of the members of this pathway and the first described member of the JAK family. TYK2 associates with inflammatory and autoimmune diseases, cancer and diabetes. Here, we present novel compounds as selective inhibitors of the canonical kinase domain of TYK2 enzyme. These compounds were rationally designed and synthesized with appropriate reactions. Molecular modeling techniques were used to design and optimize the candidates for TYK2 inhibition and to determine the estimated binding orientations of them inside JAKs. Designed compounds potently inhibited TYK2 with good selectivity against other JAKs as determined by in vitro assays. In order to verify its selectivity properties, compound A8 was tested against 58 human kinases (KinaseProfiler™ assay). The effects of the selected seven compounds on the protein levels of members of the JAK/STAT family were also detected in THP-1 monocytes although the basal level of these proteins is poorly detectable. Therefore, their expression was induced by lipopolysaccharide treatment and compounds A8, A15, A18, and A19 were found to be potent inhibitors of the TYK2 enzyme, (9.7 nM, 6.0 nM, 5.0 nM and 10.3 nM, respectively), and have high selectivity index for the JAK1, JAK2, and JAK3 enzymes. These findings suggest that triazolo[1,5-a]pyrimidinone derivatives may be lead compounds for developing potent TYK2-selective inhibitors targeting enzymes' active site.

Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2.

Deciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we leverage TurboID-based proximity labeling coupled with affinity purification-mass spectrometry to comprehensively map the proximal human proteomes of all seven canonical type I IFN signaling cascade members under basal and IFN-stimulated conditions. This uncovers a network of 103 high-confidence proteins in close proximity to the core members IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT2, and IRF9, and validates several known constitutive protein assemblies, while also revealing novel stimulus-dependent and -independent associations between key signaling molecules. Functional screening further identifies PJA2 as a negative regulator of IFN signaling via its E3 ubiquitin ligase activity. Mechanistically, PJA2 interacts with TYK2 and JAK1, promotes their non-degradative ubiquitination, and limits the activating phosphorylation of TYK2 thereby restraining downstream STAT signaling. Our high-resolution proximal protein landscapes provide global insights into the type I IFN signaling network, and serve as a valuable resource for future exploration of its functional complexities.

Evaluation of IFNAR2 and TYK2 transcripts' prognostic role in COVID-19 patients: a retrospective study.

Background and objectives: This study aimed to investigate the possible prognostic significance of interferon alpha-beta receptor subunit 2 (IFNAR2) and tyrosine kinase 2 (TYK2) expressions. Methods: We conducted a retrospective study including COVID-19 adult patients. All blood samples were collected before any interventions. The expressions of IFNAR2 and TYK2 were assessed using real-time PCR in venous blood samples of 54 cases and 56 controls. The transcript quantities of IFNAR2 and TYK2 genes were assessed using a Delta-Ct method. Results: Our findings show no significant differences in gene expression levels for IFNAR2 and TYK2 between patients who required oxygen (O2) therapy and those who did not (p-value = 0.732 and p-value = 0.629, respectively). Likewise, there were no significant differences in IFNAR2 and TYK2 expressions between patients hospitalized for less than 7 days and those hospitalized for 7 days or more (p-value = 0.455 and p-value = 0.626, respectively). We also observed a weak correlation between IFNAR2 expression and CRP (p-value = 0.045, r = 0.192). There was a negative correlation between the expression levels of IFNAR2 and TYK2 transcripts in COVID-19 patients (p-value = 0.044; partial correlation coefficient = -0.283). Additionally, IFNAR2 and TYK2 were significantly downregulated in the COVID-19 group compared to healthy subjects (p-value = 0.002 and p-value = 0.028, respectively). However, neither IFNAR2 nor TYK2 expression was significantly different between the case subgroups based on COVID-19 severity. The IFNAR2 ΔΔCt (B = -0.184, 95% CI: -0.524-0.157, p-value = 0.275) and the TYK2 ΔΔCt (B = 0.114, 95% CI: -0.268-0.496, p-value = 0.543) were not found to be significant predictors of hospitalization duration. The area under the curve (AUC) for IFNAR2 expression is 0.655 (p-value = 0.005, 95% CI: 0.554-0.757), suggesting its poor discriminative value. Conclusion: We were unable to comment definitively on the prognostic power of IFNAR2 and TYK2 expressions in COVID-19 patients, and larger-scale studies are needed. The principal limitations of this study included the lack of longitudinal analysis and limited sample size.

TYK2, IFITM3, IFNAR2 and OAS3 single-nucleotide polymorphisms among severe COVID-19 ICU patients in Morocco.

OBJECTIVES: This study aimed to explore the potential correlation between specific single nucleotide polymorphisms (TYK2, IFITM3, IFNAR2, and OAS3 variants) and the severity of COVID-19 in Moroccan patients. METHODS: A genetic analysis was conducted on 109 patients with PCR-confirmed SARS-CoV-2 infection in Morocco. Among these patients, 46% were hospitalized in the intensive care unit, while 59% were not hospitalized. Importantly, all patients lacked known risk factors associated with COVID-19 severity. Genotyping was performed to identify variations in TYK2 rs74956615, IFITM3 rs12252, IFNAR2 rs2236757, and OAS3 rs10735079. Statistical analysis was applied using codominant, dominant and recessive logistic regression models to assess correlations with COVID-19 severity. RESULTS: Our findings revealed no significant correlation between TYK2 rs74956615, IFITM3 rs12252, IFNAR2 rs2236757, and OAS3 rs10735079 with COVID-19 severity in Moroccan patients, as indicated in logistic regression models (p > .05). Interestingly, these results may offer insights into the mitigated impact of the COVID-19 pandemic and the reduced severity observed in SARS-CoV-2 infected patients in Morocco. Age, however, exhibited a significant correlation with severity (p < .001), with a trend towards increased likelihood of ICU admission with advancing age. Additionally, In the severe group, a higher proportion of patients were females (54%), indicating a statistically significant correlation with disease severity (p = .04). Nevertheless, female ICU patients aged above 60 years accounted for 37%, compared to 17% for males. CONCLUSION: This study underscores the absence of a genetic association between the selected polymorphisms and COVID-19 severity in Moroccan patients. Advanced age emerges as the primary factor influencing the severity of COVID-19 patients without comorbidities. We recommend setting the threshold for advanced age at 60 years as a risk factor for severe forms of COVID-19.

The Psoriasis Treatment Pipeline: An Overview and Update.

Significant research advances in our understanding of psoriatic disease have led to the development of several highly selective, effective, and safe topical and systemic treatments. These treatments have led to unprecedented levels of disease clearance and control for most patients with psoriasis with cutaneous disease. However, there remains a need for improved treatments for those patients with recalcitrant disease, psoriatic arthritis, or nonplaque disease variants. Recently approved therapies and investigational products in ongoing clinical development programs that target IL-17A/F, IL-23, TYK2, PDE4, AhR or IL-36 cytokine signaling are improving the clinician's ability to care for a broader range of patients affected by psoriasis.

Tyrosine kinase 2 modulates splenic B cells through type I IFN and TLR7 signaling.

Tyrosine kinase 2 (TYK2) is involved in type I interferon (IFN-I) signaling through IFN receptor 1 (IFNAR1). This signaling pathway is crucial in the early antiviral response and remains incompletely understood on B cells. Therefore, to understand the role of TYK2 in B cells, we studied these cells under homeostatic conditions and following in vitro activation using Tyk2-deficient (Tyk2-/-) mice. Splenic B cell subpopulations were altered in Tyk2-/- compared to wild type (WT) mice. Marginal zone (MZ) cells were decreased and aged B cells (ABC) were increased, whereas follicular (FO) cells remained unchanged. Likewise, there was an imbalance in transitional B cells in juvenile Tyk2-/- mice. RNA sequencing analysis of adult MZ and FO cells isolated from Tyk2-/- and WT mice in homeostasis revealed altered expression of IFN-I and Toll-like receptor 7 (TLR7) signaling pathway genes. Flow cytometry assays corroborated a lower expression of TLR7 in MZ B cells from Tyk2-/- mice. Splenic B cell cultures showed reduced proliferation and differentiation responses after activation with TLR7 ligands in Tyk2-/- compared to WT mice, with a similar response to lipopolysaccharide (LPS) or anti-CD40 + IL-4. IgM, IgG, IL-10 and IL-6 secretion was also decreased in Tyk2-/- B cell cultures. This reduced response of the TLR7 pathway in Tyk2-/- mice was partially restored by IFNα addition. In conclusion, there is a crosstalk between TYK2 and TLR7 mediated by an IFN-I feedback loop, which contributes to the establishment of MZ B cells and to B cell proliferation and differentiation.

JAK-STAT signaling maintains homeostasis in T cells and macrophages.

Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice-but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse gene-regulatory programs, including effects of STAT2 and IRF9 that were independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wild-type mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcriptional state and helps prepare these cells for rapid response to immune stimuli.

TYK2 inhibition with deucravacitinib ameliorates erosive oral lichen planus.

Erosive oral lichen planus (OLP) is a challenging disease. This T cell driven disorder frequently shows a treatment unresponsive course and strongly limits patients' quality of life. The disease lacks FDA or EMA approved drugs for its treatment and the efficacy of the commonly administered treatments (i.e. topical and systemic steroids, steroid sparing agents) is often only partial. Although the etiopathogenesis of the disease still needs to be fully elucidated, recent advances helped to identify interferon-É£ (IFN-É£) as a pivotal cytokine in OLP pathogenesis, thus making the interference with its signalling a therapeutic target. Janus kinase (JAK) inhibitors therefore gained relevance for their inhibitory effect on IFN-É£ signalling. While some drugs such as abrocitinib, upadacitinib, tofacitinib directly interfere with IFN-É£ signalling through blockade of JAK1 and/or JAK2, deucravacitinib, a selective TYK-2 inhibitor indirectly interferes on IFN-É£ activation through interference with interleukin (IL)-12, a potent promotor for Th1/IFN-É£ responses. This mechanism of action makes deucravacitinib a candidate drug for the treatment of OLP. Here we provide initial evidence that deucravacitinib 6 mg daily has a beneficial effect in three patients with oral OLP.

TYK2: an emerging therapeutic target in rheumatic disease.

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family of intracellular signalling molecules. By participating in signalling pathways downstream of type I interferons, IL-12, IL-23 and IL-10, TYK2 elicits a distinct set of immune events to JAK1, JAK2 and JAK3. TYK2 polymorphisms have been associated with susceptibility to various rheumatic diseases including systemic lupus erythematosus and dermatomyositis. In vitro and animal studies substantiate these findings, highlighting a role for TYK2 in diseases currently managed by antagonists of cytokines that signal through TYK2. Various inhibitors of TYK2 have now been studied in human disease, and one of these inhibitors, deucravacitinib, has now been approved for the treatment of psoriasis. Phase II trials of deucravacitinib have also reported positive results in the treatment of psoriatic arthritis and systemic lupus erythematosus, with a preliminary safety profile that seems to differ from that of the JAK1, JAK2 and JAK3 inhibitors. Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are also in earlier stages of clinical trials. Overall, TYK2 inhibitors hold promise for the treatment of a distinct spectrum of autoimmune diseases and could potentially have a safety profile that differs from other JAK inhibitors.

Employing zero-inflated beta distribution in an exposure-response analysis of TYK2/JAK1 inhibitor brepocitinib in patients with plaque psoriasis.

Brepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with moderate-to-severe plaque psoriasis were utilized to develop a population exposure-response model that can be employed to inform dose selection decisions for further clinical development. A modeling approach that employs the zero-inflated beta distribution was used to account for the bounded nature and distributional characteristics of the Psoriasis Area and Severity Index (PASI) score data. The developed exposure-response model provided an adequate description of the observed PASI scores across all the treatment arms tested and across both the induction and maintenance dosing periods of the study. In addition, the developed model exhibited a good predictive capacity with regard to the derived responder metrics (e.g., 75%/90%/100% improvement in PASI score [PASI75/90/100]). Clinical trial simulations indicated that the induction/maintenance dosing paradigm explored in this study does not offer any advantages from an efficacy perspective and that doses of 10, 30, and 60 mg once-daily may be suitable candidates for clinical evaluation in subsequent Phase 2b studies.

TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes.

Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in ß-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in ß-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.

Associations of genetic variants within TYK2 with pulmonary tuberculosis among Chinese population.

BACKGROUND: Pulmonary tuberculosis (PTB) is a common infectious disease caused by mycobacterium tuberculosis (MTB) and the present study aims to explore the associations of genetic variants within tyrosine kinases 2 (TYK2) with PTB incidence. METHODS: A population-based case control study including 168 smear-positive PTB cases and 251 controls was conducted. Five single nucleotide polymorphisms (SNPs) including rs280520, rs91755, rs2304256, rs12720270, rs280519 located within TYK2 gene were selected and MassARRAY® MALDI-TOF system was employed for genotyping. SPSS 19.0 was adopted for statistical analysis, non-conditional logistic regression was conducted. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed to estimate their contributions to PTB incidence. RESULTS: In the overall study population, rs91755 TT and rs280519 AA genotypes were found to be associated with reduced PTB risk (OR = 0.34, 95% CI: 0.16-0.72; OR = 0.38, 95% CI: 0.18-0.79, respectively). After stratification for sex, we found that among the male population, rs91755TG/TT, rs12720270AG/GG and rs280519AG/AA genotypes were associated with reduced PTB risk (OR = 0.41, 95% CI: 0.21-0.80; OR = 0.44, 95% CI: 0.21-0.94; OR = 0.42, 95% CI: 0.21-0.82, respectively). After stratification for age, we found that among those aged <60 years, rs91755TT and rs280519AA genotype were associated with reduced PTB risk (OR = 0.29, 95% CI: 0.09-0.90; OR = 0.34, 95% CI: 0.11-1.08, respectively); while rs2304256AC/AA genotype was associated with increased PTB risk (OR = 2.68, 95% CI: 1.05-6.85). Haplotype analysis revealed that AGAAG and ATCGA (Combined with rs280520, rs91755, rs2304256, rs12720270 and rs280519) were associated with increased (OR = 1.54, 95% CI: 1.01-2.37) and decreased PTB risk (OR = 0.70, 95% CI: 0.52-0.94), respectively. CONCLUSIONS: The genetic variants located within TYK2 including rs91755, rs12720270 and rs280519 were found to be associated with modified PTB risk and the SNPs had potential to be the biomarkers to predict PTB incidence risk.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, in Japanese patients with moderate to severe plaque, erythrodermic, or generalized pustular psoriasis: Efficacy and safety results from an open-label, phase 3 trial.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in Japan for adult patients with plaque (PP), generalized pustular (GPP), and erythrodermic (EP) psoriasis who have had an inadequate response to conventional systemic therapies. This approval is based on results from the global phase 3 POETYK PSO-1 and PSO-2 trials in which deucravacitinib was associated with significantly improved efficacy outcomes compared with placebo in adults with moderate to severe plaque psoriasis, and results described here from POETYK PSO-4, an open-label, single-arm, phase 3 trial (NCT03924427), which evaluated the efficacy and safety of deucravacitinib 6 mg once daily in adult Japanese patients with PP, GPP, or EP. The coprimary endpoints were the proportion of patients achieving a ≥75% reduction from baseline in the Psoriasis Area and Severity Index (PASI 75) and a static Physician's Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1) with at least a two-point improvement from baseline at week 16. Nonresponder imputation was used for missing data. Efficacy responses, adverse events (AEs), and serious AEs (SAEs) were recorded for up to 52 weeks. Seventy-four patients were treated (PP, n = 63; GPP, n = 3; EP, n = 8). At week 16, 76.2%, 66.7%, and 37.5% of patients with PP, GPP, and EP, respectively, had achieved PASI 75, and 82.5%, 0.0%, and 50.0% had achieved sPGA 0/1. Responses were overall maintained through week 52. AEs occurred in 74.6% of patients with PP, 100% of patients with GPP, and 87.5% of patients with EP. The most common AEs were nasopharyngitis and acne. Rates of SAEs and discontinuations were low. There were no deaths. Deucravacitinib was effective and well tolerated in Japanese patients with moderate to severe PP and in a limited number of patients with GPP or EP.

Deucravacitinib: The First FDA-Approved Oral TYK2 Inhibitor for Moderate to Severe Plaque Psoriasis.

OBJECTIVE: The objective of this study was to review the safety and efficacy of deucravacitinib, a tyrosine kinase 2 (TYK2) inhibitor for moderate to severe plaque psoriasis. DATA SOURCES: Literature was reviewed from MEDLINE and Clinicaltrials.gov up to December 2022 using the terms "deucravacitinib" and "BMS-986165." STUDY SELECTION: Relevant articles in English relating to the pharmacodynamics, pharmacokinetics, efficacy, and safety of deucravacitinib were included. A total of 6 trial results were included. STUDY SELECTION AND DATA EXTRACTION: Deucravacitinib showed clinical efficacy across all the phase II and III clinical trials. Excluding the long-term extension study, there were 2248 subjects across all studies, with 63.2% of patients receiving deucravacitinib 6 mg daily. Of these subjects, the average proportion achieving a PASI 75 (a reduction of greater than 75% in the Psoriasis Area and Severity Index) at week 16 was 65.1%. Patients receiving deucravacitinib 6 mg once daily had a higher rate of achieving both PASI 75 response and a Static Physician's Global Assessment (sPGA) score of 0 or 1, compared with oral apremilast 30 mg twice daily. The safety profile of deucravacitinib includes mild adverse events (AEs), most commonly nasopharyngitis, with serious AEs reported ranging from 1.35% to 9.5%. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING MEDICATIONS: While many available therapies for moderate to severe plaque psoriasis rely on an injectable dosage form or extensive monitoring, deucravacitinib can potentially reduce patient medication-related burden. This review summarizes the efficacy and safety of oral deucravacitinib for the treatment of severe plaque psoriasis. CONCLUSION: Deucravacitinib shows a consistent efficacy and safety profile as the first oral TYK2 inhibitor approved for adult patients with moderate to severe plaque psoriasis who are eligible for systemic therapy or phototherapy treatment.

CALCRL induces resistance to daunorubicin in acute myeloid leukemia cells through upregulation of XRCC5/TYK2/JAK1 pathway.

Chemotherapy is the main treatment option for acute myeloid leukemia (AML), but acquired resistance of leukemic cells to chemotherapeutic agents often leads to difficulties in AML treatment and disease relapse. High calcitonin receptor-like (CALCRL) expression is closely associated with poorer prognosis in AML patients. Therefore, this study was performed by performing CALCRL overexpression constructs in AML cell lines HL-60 and Molm-13 with low CALCRL expression. The results showed that overexpression of CALCRL in HL-60 and Molm-13 could confer resistance properties to AML cells and reduce the DNA damage and cell cycle G0/G1 phase blocking effects caused by daunorubicin (DNR) and others. Overexpression of CALCRL also reduced DNR-induced apoptosis. Mechanistically, the Cancer Clinical Research Database analyzed a significant positive correlation between XRCC5 and CALCRL in AML patients. Therefore, the combination of RT-PCR and Western blot studies further confirmed that the expression levels of XRCC5 and PDK1 genes and proteins were significantly upregulated after overexpression of CALCRL. In contrast, the phosphorylation levels of AKT/PKCε protein, a downstream pathway of XRCC5/PDK1, were significantly upregulated. In the response study, transfection of overexpressed CALCRL cells with XRCC5 siRNA significantly upregulated the drug sensitivity of AML to DNR. The expression levels of PDK1 protein and AKT/PKCε phosphorylated protein in the downstream pathway were inhibited considerably, and the expression of apoptosis-related proteins Bax and cleaved caspase-3 were upregulated. Animal experiments showed that the inhibitory effect of DNR on the growth of HL-60 cells and the number of bone marrow invasions were significantly reversed after overexpression of CALCRL in nude mice. However, infection of XCRR5 shRNA lentivirus in HL-60 cells with CALCRL overexpression attenuated the effect of CALCRL overexpression and upregulated the expression of apoptosis-related proteins induced by DNR. This study provides a preliminary explanation for the relationship between high CALCRL expression and poor prognosis of chemotherapy in AML patients. It offers a more experimental basis for DNR combined with molecular targets for precise treatment in subsequent studies.

Community analysis of large-scale molecular dynamics simulations elucidated dynamics-driven allostery in tyrosine kinase 2.

TYK2 is a nonreceptor tyrosine kinase, member of the Janus kinases (JAK), with a central role in several diseases, including cancer. The JAKs' catalytic domains (KD) are highly conserved, yet the isolated TYK2-KD exhibits unique specificities. In a previous work, using molecular dynamics (MD) simulations of a catalytically impaired TYK2-KD variant (P1104A) we found that this amino acid change of its JAK-characteristic insert (αFG), acts at the dynamics level. Given that structural dynamics is key to the allosteric activation of protein kinases, in this study we applied a long-scale MD simulation and investigated an active TYK2-KD form in the presence of adenosine 5'-triphosphate and one magnesium ion that represents a dynamic and crucial step of the catalytic cycle, in other protein kinases. Community analysis of the MD trajectory shed light, for the first time, on the dynamic profile and dynamics-driven allosteric communications within the TYK2-KD during activation and revealed that αFG and amino acids P1104, P1105, and I1112 in particular, hold a pivotal role and act synergistically with a dynamically coupled communication network of amino acids serving intra-KD signaling for allosteric regulation of TYK2 activity. Corroborating our findings, most of the identified amino acids are associated with cancer-related missense/splice-site mutations of the Tyk2 gene. We propose that the conformational dynamics at this step of the catalytic cycle, coordinated by αFG, underlie TYK2-unique substrate recognition and account for its distinct specificity. In total, this work adds to knowledge towards an in-depth understanding of TYK2 activation and may be valuable towards a rational design of allosteric TYK2-specific inhibitors.

Efficacy of tyrosine-kinase-2 and phosphodiesterase-4 inhibitors for scalp psoriasis: a systematic review and meta-analysis.

OBJECTIVES: Psoriasis of the scalp is challenging to manage. The only approved oral tyrosine kinase 2 and phosphodiesterase 4 inhibitors for psoriasis are deucravacitinib and apremilast. The aim of this study was to explore their efficacy for scalp psoriasis utilizing data from randomized controlled trials. METHODS: We searched Medline, Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov up to August 4, 2023. To determine risk of bias, the revised Risk of Bias assessment tool 2.0 was used. Inverse variance random effects meta-analyses were executed. Heterogeneity was assessed utilizing Q and I2 statistics. Pre-determined outcomes included the proportion of participants with cleared scalp skin (Scalp Physician's Global Assessment [ScPGA] of 0/1), mean change in Psoriasis Scalp Severity Index (PSSI), and mean improvement in Dermatology Life Quality Index (DLQI). RESULTS: Ten RCTs fulfilled inclusion criteria. Both apremilast (RR = 2.41, 95% CI = 2.08-2.79, Tau2 = 0, I2 = 0) and deucravacitinib (RR = 3.86, 95% CI = 3.02-4.94, Tau2 = 0, I2 = 0) were more effective in inducing ScPGA of 0/1 at 16 weeks compared to placebo. Furthermore, deucravacitinib was more effective than apremilast (RR = 1.70, 95% CI = 1.44-2.00, Tau2 = 0, I2 = 0). An analysis could not be executed for the rest of the outcomes. CONCLUSIONS: Apremilast and deucravacitinib are effective for scalp psoriasis. Deucravacitinib may be more efficient in clearing the scalp.

Deucravacitinib, a selective, allosteric tyrosine kinase 2 inhibitor, in scalp psoriasis: A subset analysis of two phase 3 randomized trials in plaque psoriasis.

BACKGROUND: Scalp involvement in plaque psoriasis is challenging to treat. OBJECTIVE: To evaluate the efficacy and safety of deucravacitinib (DEUC) in scalp psoriasis. METHODS: POETYK PSO-1 and PSO-2 were global phase 3, 52-week, double-blinded trials in adults with moderate to severe psoriasis. Patients were randomized 1:2:1 to oral placebo, DEUC 6 mg once daily, or apremilast 30 mg twice daily. This pooled secondary analysis evaluated scalp-specific Physician Global Assessment score of 0 or 1 (0/1), ≥90% improvement from baseline in Psoriasis Scalp Severity Index, and change from baseline in Psoriasis Scalp Severity Index. Adverse events were evaluated through week 16. RESULTS: Overall, 1084 patients with moderate to severe scalp psoriasis at baseline were included. At week 16, response rates were greater with DEUC versus placebo or apremilast for scalp-specific Physician Global Assessment 0/1 (64.0% vs 17.3% vs 37.7%; P < .0001), ≥90% improvement from baseline in Psoriasis Scalp Severity Index (50.6% vs 10.5% vs 26.1%; P < .0001), and change from baseline in Psoriasis Scalp Severity Index. Responses were maintained through 52 weeks with continuous DEUC. Safety was consistent with the entire study population. LIMITATIONS: Lack of data in milder scalp psoriasis. CONCLUSION: DEUC was significantly more efficacious than placebo or apremilast in improving moderate to severe scalp psoriasis and was well tolerated.