Tyk2 JH2 (IC50 = 0.2 nM); JAK1 JH2 (IC50 = 1 nM)

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of Deucravacitinib (BMS-986165)(11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases [1].
Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1]. Potential benefits of compounds with deuteration: Longer half-life in living things. Deuterated compounds might be able to increase the compound's pharmacokinetic properties, or in vivo half-life. This can facilitate administration and enhance the compound's safety, effectiveness, and tolerance. Boost oral bioavailability, second. Greater amounts of the unmetabolized medicine are able to reach their target of action because deuterated substances lessen the amount of undesired metabolism (first-pass metabolism) in the liver and intestinal wall. Better tolerance and activity at low doses are determined by high bioavailability. (3) Enhance the properties of metabolism. Deuterated substances can enhance medication metabolism and lessen the production of hazardous or reactive metabolites. (4) Enhance the security of medications. Deuterated chemicals are harmless and can lessen or eliminate the undesirable side effects of medicinal substances. (5) Preserve the treatment outcome. According to earlier research, deuterated molecules should maintain biological potency and selectivity comparable to hydrogen analogs.

Lupus-like disease is strongly inhibited in NZB/W mice treated with Tyk2-IN-4. Tyk2-IN-4 is safe and overall well-tolerated. There are no serious adverse events and the frequency of non-serious adverse events are similar in the active (75%) and placebo (76%) groups. After oral administration, Tyk2-IN-4 is rapidly absorbed and exhibits an apparent elimination half-life of 8-15 hours[1].

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In mice, 11/Deucravacitinib (BMS-986165) was evaluated in a skin inflammation (psoriasis-like) model of IL-23-driven acanthosis whereby repetitive intradermal injections of IL-23 into the ears of mice induces a profound epidermal hyperplasia (acanthosis) and inflammatory cellular infiltration mediated by Th17 cells and IL-22, similar to the underlying mechanisms in psoriasis (Figure 6). In this model, 11/Deucravacitinib (BMS-986165) dose-dependently protects from IL-23-induced acanthosis in mice, with the 15 mg/kg oral dose of 11 administered twice-daily for 9 days proving to be as effective as an anti-IL-23 adnectin as a positive control (Figure 6a). The 30 mg/kg twice-daily oral dose is more effective than the anti-IL-23 adnectin at providing protection. Histological evaluation shows that the epidermal hyperplasia and the inflammatory cellular infiltration is also inhibited in a dose-dependent manner, with the high dose of 30 mg/kg twice daily providing protection more effectively than the anti-IL-23 adnectin positive control (Figure 6b). Quantitative polymerase chain reaction (PCR) analysis of skin biopsies reveals 11 to be quite effective at blocking inflammatory cytokine expression, including IL-17A, IL-21, and subunits of IL-12 and IL-23 (Figure 6c). PK measurements on study animals shows that the 7.5, 15, and 30 mg/kg twice-daily doses provides drug levels at or above the in vitro mouse whole blood IC50 value of 100 nM (IFNα-induced pSTAT1) for 19, 21, and 24 h, respectively. In addition to preclinical models of psoriasis, 11 has also been shown to be highly efficacious in murine models of colitis and lupus. These results demonstrate in an anti-CD40-induced colitis model in severe-combined-immunodeficient-diseased (SCID) mice, 11 administered 50 mg/kg twice-daily provides inhibition of peak weight loss (IL-12 driven) by 99% and inhibition of histological scores by 70% comparable to an anti-p40 monoclonal antibody control. Furthermore, when orally administered up to a maximum 30 mg/kg once-daily dose in a three-month lupus disease model using NZB/W lupus-prone mice, 11 is well-tolerated and highly efficacious in protecting from nephritis. In this latter study, efficacy is well-correlated with inhibition of type I IFN-dependent gene expression in both whole blood and kidneys in study mice and is at least as effective as a blocking anti-IFNαR antibody [1].

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Interferon‐responsive genes expression following IFNα‐2a challenge [2]
IRG induction began ~3 h following in vivo challenge with a clinical dose of IFNα‐2a given 2 h after the morning dose of Deucravacitinib (BMS-986165) or placebo, as demonstrated by induction of the oligoadenylate synthetase‐like (OASL) gene, a typical IRG (data not shown). IRG induction was robust in placebo‐administered volunteers, with most genes being induced by more than 10‐fold. Of the 53 target genes assessed, 52 were included in the analysis, as complement component 1q (C1Q) was found not to be induced immediately by IFN administration but was induced at the 26‐h timepoint, and thus was considered unlikely to be a direct target for IFN‐induced gene expression. Compared with the placebo group, the expression of all 52 genes included in the aggregation was robustly inhibited in a dose‐dependent manner by prior administration of deucravacitinib (Figure 3); C1Q expression was inhibited 26 h after challenge. Exposures of IFNα‐2a increased in a deucravacitinib dose‐dependent manner, thus, consumption of IFNα‐2a was inhibited by blocking signal transduction. This paradoxical increase in IFNα‐2a appears to be an additional PD measure of deucravacitinib (data not shown).

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2 [1].

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All biochemical potencies and selectivities were determined using homogeneous time-resolved fluorescence (HTRF) assays where compounds were shown to compete with a fluorescent probe for binding to human recombinant JAK1, JAK2, JAK3, and TYK2 JH1 domain proteins in addition to TYK2 and JAK1 JH2 protein domains. Dose–response curves were generated to determine the concentration required for inhibiting 50% of the HTRF signal (IC50) as derived by nonlinear regression analysis. Cellular potencies and selectivities were determined using stably integrated STAT-dependent luciferase reporter assays in T-cells using IFNα-stimulation for measuring TYK2/JAK1 dependent signaling and IL-23 stimulation for measuring TYK2/JAK1 dependent signaling. JAK2 dependent signaling was measured in TF-1 cells using GM-CSF stimulation. Dose–response curves were generated to determine the concentration required to inhibit 50% of cellular response (IC50) as derived by nonlinear regression analysis. Potencies and selectivities for JAK-dependent signaling were also measured in human and mouse whole blood using specific cytokine stimulations and measuring the phosphorylation of specific STAT proteins by cellular staining and flow cytometry. Experimental details for all assays have been previously reported. All compounds active in biological assays were electronically filtered for structural attributes common to pan assay interference compounds (PAINS) and were found to be negative [1].

Cellular potencies and selectivities were determined using stably integrated STAT-dependent luciferase reporter assays in T-cells using IFNα-stimulation for measuring TYK2/JAK1 dependent signaling and IL-23 stimulation for measuring TYK2/JAK1 dependent signaling. JAK2 dependent signaling was measured in TF-1 cells using GM-CSF stimulation. Dose–response curves were generated to determine the concentration required to inhibit 50% of cellular response (IC50) as derived by nonlinear regression analysis. Potencies and selectivities for JAK-dependent signaling were also measured in human and mouse whole blood using specific cytokine stimulations and measuring the phosphorylation of specific STAT proteins by cellular staining and flow cytometry. Experimental details for all assays have been previously reported. All compounds active in biological assays were electronically filtered for structural attributes common to pan assay interference compounds (PAINS) and were found to be negative[1].

IL-23-Induced Acanthosis in Mice [1]
Acanthosis was induced in 6–8-week-old C57BL/6 female mice (19–20 g average weight, Jackson Laboratories) by intradermal injection of dual chain, recombinant human IL-23 into the right ear. IL-23 injections were administered every other day from day 0 through day 9 of the study. Treatment groups consisted of eight mice per group. Compound 11/Deucravacitinib (BMS-986165) at 7.5, 15, and 30 mg/kg BID in vehicle (EtOH:TPGS:PEG300, 5:5:90) and vehicle alone dosed BID by oral gavage, with the first dose given the evening before the first IL-23 injection. An anti-IL-23 adnectin (3 mg/kg) and PBS control were administered subcutaneously approximately 1 h prior to the first IL-23 injection and then twice a week thereafter. Ear thickness was measured using a Mitutoyo dial caliper and calculated as the percent change in thickness from the baseline measurement taken on day 0 before initial IL-23 injections for each animal. At the end of the study, IL-23-injected ears as well as naïve control ears were collected from four animals per group for histological examination and gene expression analyses. Terminal blood samples collected via the retro-orbital sinus were used for PK determinations. Statistical analyses were performed using Student’s t tests or ANOVA with Dunnett’s post test. At the end of the study, ears were removed and fixed in 10% neutral-buffered formalin for 24–48 h. The fixed ears were then cut longitudinally, and two pieces were parallel embedded to make the paraffin blocks. The paraffin blocks were then sectioned and placed on microscope slides for H&E staining for histological evaluation. Severity of ear inflammation was scored using an objective scoring system based on the following parameters: extent of the lesion, severity of hyperkeratosis, number and size of pustules, height of epidermal hyperplasia (acanthosis, measured in interfollicular epidermis), and the amount of inflammatory infiltrate in the dermis and soft tissue. The latter two parameters, acanthosis and inflammatory infiltrate, were scored independently on a scale from 0 to 4: 0, none; 1, minimal; 2, mild; 3, moderate; 4, marked. The histological changes were blindly evaluated by a pathologist. Statistical analyses was performed using one-way ANOVA with Dunnett’s test for comparison of each treatment versus the vehicle control.

Absorption, Distribution and Excretion
In healthy subjects, after oral administration, the plasma Cmax and AUC of deucravacitinib increased proportionally within a dose range of 3 mg to 36 mg (equivalent to 0.5 to 6 times the approved recommended dose). Following a once-daily dose of 6 mg deucravacitinib, its steady-state Cmax and AUC24 were 45 ng/mL and 473 ng·hr/mL, respectively. Following a once-daily dose of the active metabolite of deucravacitinib, BMT-153261, its steady-state Cmax and AUC24 were 5 ng/mL and 95 ng·hr/mL, respectively. The absolute oral bioavailability of deucravacitinib was 99%, with a median Tmax of 2 to 3 hours. A high-fat, high-calorie diet reduced the Cmax and AUC of declavatinib by 24% and 11%, respectively, and prolonged the Tmax by 1 hour; however, this had a significant clinical impact on drug absorption and exposure. Following a single dose of radiolabeled declavatinib, approximately 13% and 26% of the dose were excreted unchanged in urine and feces, respectively. Approximately 6% and 12% of the dose as BMT-153261 were detected in urine and feces, respectively. The steady-state volume of distribution of declavatinib is 140 L. The renal clearance of declavatinib ranges from 27 to 54 mL/min. Metabolites/Metabolites: Declavatinib undergoes N-demethylation mediated by cytochrome P-450 (CYP) 1A2 to generate the major metabolite BMT-153261, which has pharmacological activity comparable to the parent drug. However, the circulating exposure to BMT-153261 accounts for approximately 20% of the total systemic exposure to drug-related components. Deucravacitinib is also metabolized by CYP2B6, CYP2D6, carboxylesterase (CES) 2, and uridine glucuronyl transferase (UGT) 1A9.

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Biological Half-Life
The terminal half-life of Deucravacitinib is 10 hours.

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Triazole 11/Deucravacitinib (BMS-986165) showed extremely low metabolic defects, excellent pharmacokinetic properties, and high efficacy in models of inflammation and autoimmune diseases[1]
11/Deucravacitinib (BMS-986165) has shown excellent potency and functional selectivity for TYK2-dependent responses, and further in vitro analysis showed that it has extremely low metabolic defects and acceptable pharmacokinetic properties, making it suitable for further development (Table 7). After incubation in liver microsomes, the drug showed excellent stability in a variety of species, including humans, mice, rats, monkeys, dogs, and rabbits (T1/2 > 120 min). Good permeability was also observed in Caco-2 cell experiments, with moderate efflux (Pc = 73 nm/s from apex to basal side; Pc = 740 nm/s from basal side to apex; efflux ratio approximately 10). Drug interaction (DDI) assessment indicated a low overall risk, as no significant inhibition of multiple cytochrome P450 (CYP) isoenzymes (1A2, 2C9, 2C19, 2D6, and 3A4) or induction of CYP3A4 was observed at the highest tested concentration (40 μM). In hERG potassium channel patch-clamp assays, compound 11 showed low inhibition (26 ± 11% at 10 μM), suggesting a low cardiovascular risk associated with QTc interval prolongation. Its protein binding was moderate in multiple species, including humans, monkeys, and mice (12%–15% in the free state). The water solubility of the crystalline free base form of compound 11 is low (5.2 μg/mL), but sufficient for preclinical studies. In preclinical studies across multiple species, the overall pharmacokinetic parameters of compound 11 were favorable (Table 8). Consistent with the low metabolic rate (T1/2 > 120 min) observed in microsomal metabolism assays, compound 11 was cleared in mice, dogs, and monkeys at low to moderate levels, with clearances of 13.2, 6.8, and 4.8 mL min–1 kg–1, respectively. The compound exhibited a low volume of distribution (Vss) in the range of 2–3 L/kg and a moderate half-life of approximately 4–5 hours (across species). Upon oral administration of 10 mg/kg, compound 11 was well absorbed in mice, dogs, and monkeys, with high exposure and bioavailability (%F > 85%). In these studies, the concentrations of the circulating primary amide metabolite generated from the N-dealkylation of the deuterium methylamide of compound 11 were near the limit of detection (<2 nM), consistent with previous reports in this series of studies demonstrating the effective blockade of this metabolic pathway by deuteration.

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Pharmacokinetics in healthy volunteers[2]
After administration, Deucravacitinib (BMS-986165) was rapidly absorbed, with an apparent elimination half-life (t_1/2) of 7.9–15.0 hours after a single dose and an average effective half-life (t_1/2) of 7.5–13.1 hours after multiple doses (Figure 1, Table 1). After a single dose (the highest dose in the SAD group was 10 mg), C_max and AUCINF increased nonproportionally with increasing dose, but showed an apparent dose-proportionate increase at doses ≥10 mg. Similar pharmacokinetic characteristics were observed after multiple doses in the MAD group, showing a dose-proportionate relationship at doses ≥4 mg bid. Moderate drug accumulation (1.4–1.9-fold) was observed after multiple doses, reaching steady state on day 5, the day the first Cmin sample was collected. Urinary recovery of unmetabolized deucravacitinib was assessed only in the SAD group, with recovery rates ranging from 10% to 15% across all dose groups; renal clearance of deucravacitinib ranged from 27.5 to 54.2 ml/min across the entire dose range.

Hepatotoxicity
In the pre-registration clinical trial of deucravacitinib, which included data from 1519 participants, only 1.8% of patients experienced serum ALT or AST levels exceeding 5 times the upper limit of normal. These elevations were considered unlikely to be drug-induced liver injury; most were due to myositis, and a minority were due to underlying alcoholic or non-alcoholic fatty liver disease. In a 24-week trial, 1.1% to 1.3% of patients in the deucravacitinib group experienced ALT levels exceeding 3 times the upper limit of normal, compared to 1.2% in the placebo group. Although no cases of hepatitis B virus reactivation occurred in patients treated with deucravacitinib, patients with a prior presence of HBsAg in their serum were excluded from enrollment, and most treatment courses were of limited duration. Since its approval and widespread clinical use, there have been no reports of clinically significant liver injury due to declavatinib, but the drug's market availability is limited.
Probability Score: E (Suspected but unconfirmed clinically evident cause of liver injury, including hepatitis B virus reactivation).

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Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding the use of declavatinib during lactation. Because this drug binds to plasma proteins at a rate exceeding 80%, its concentration in breast milk may be low. However, it is well absorbed orally. If a mother of an older infant requires declavatinib, this is not a reason to discontinue breastfeeding, but alternative medications may be preferred until more data are available, especially during the nursing of newborns or premature infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.
◈ What is declavatinib?
Declavatinib is a drug approved for the treatment of moderate to severe plaque psoriasis. The MotherToBaby website provides information sheets on psoriasis and psoriatic arthritis at: https://mothertobaby.org/fact-sheets/psoriasis-and-pregnancy/. Declavatinib is marketed as SOTYKTU™. Sometimes, when people find out they are pregnant, they consider changing their medication regimen or even stopping it entirely. However, it is essential to consult your healthcare provider before changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating the condition during pregnancy.
◈ I am taking declavatinib. Will it affect my pregnancy?
There is currently no research indicating that declavatinib affects pregnancy.
◈ Does taking declavatinib increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. There is currently no research determining whether declavatinib increases the risk of miscarriage.
◈ Does taking declavatinib increase the risk of birth defects?
There is a 3-5% risk of birth defects in the fetus with each pregnancy; this is known as background risk. No studies have been conducted on the relationship between deucravacitinib and human pregnancy. Animal studies reported by the manufacturer have not found an increased risk of birth defects.
◈ Does taking deucravacitinib during pregnancy increase the risk of other pregnancy-related problems?
There are currently no studies determining whether deucravacitinib increases the risk of pregnancy-related problems such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 2500 grams).
◈ Will taking deucravacitinib during pregnancy affect the child's future behavior or learning?
There are currently no studies determining whether deucravacitinib causes behavioral or learning problems in children.
◈ Breastfeeding while taking deucravacitinib:
The use of deucravacitinib during breastfeeding has not been studied. Please consult your healthcare provider about all questions regarding breastfeeding.
◈ Does the use of declavatinib by men affect fertility (the ability to impregnate a partner) or increase the risk of birth defects in the fetus during pregnancy?
Currently, there are no studies investigating whether declavatinib affects male fertility or increases the risk of birth defects in the fetus during pregnancy. Generally, exposure to the drug by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please refer to the "Paternal Exposure" information sheet on the MotherToBaby website at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
Declavatinib has a protein binding rate of 82% to 90%, with a blood concentration to plasma concentration ratio of 1.26.

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Toxicity Overview
Currently, there are no clinical data on declavatinib overdose. If any patient experiences an overdose, it is recommended to contact the poisoning assistance hotline for further treatment according to the drug overdose management protocol. Hemodialysis removes only a small amount of declavatinib, with each dialysis session removing a maximum of 5.4% of the dose, thus limiting its use in treating declavatinib overdose or toxicity. Multiple rate-model studies have shown that in male or female rats, oral doses up to 15 mg/kg/day (51 times the maximum recommended human dose based on AUC comparison) of declavatinib did not exhibit carcinogenicity. In female rats, oral doses up to 50 mg/kg/day (171 times the maximum recommended human dose based on AUC comparison) of declavatinib had no effect on reproductive parameters such as mating, fertility, or early embryonic development. In male rats, oral doses up to 50 mg/kg/day of declavatinib had no effect on mating, sperm morphology, fertility, or early embryonic parameters of their offspring; this dose was 224 times the MRHD derived from AUC comparison. In the SAD cohort, adverse events were reported in 11 volunteers treated with deucravacitinib (36.7%) and 4 volunteers treated with placebo (40%); the most common adverse event reported by preferred terminology was headache (deucravacitinib group: 5 volunteers, 16.7%; placebo group: 2 volunteers, 20.0%). Seven gastrointestinal adverse events (categorized by systemic order) were reported in the deucravacitinib group, while none were reported in the placebo group. The most common adverse event was dyspepsia, reported by 3 volunteers (10%). All adverse events were mild except for one case of moderate syncope in the placebo group. The most common all-cause adverse events in the SAD cohort are summarized in Table 2. [2]
In the MAD cohort, all adverse events were mild to moderate in severity, and the overall incidence of adverse events was similar in the declavatinib group (37 volunteers, 82%) and the placebo group (13 volunteers, 87%). The most common adverse events reported by preferred terminology in the declavatinib and placebo groups were: headache (11 volunteers, 24.4%; 5 volunteers, 33.3%), rash (9 volunteers, 20%; 2 volunteers, 13.3%), upper respiratory tract infection (8 volunteers, 17.8%; 3 volunteers, 20.0%), acne (6 volunteers, 13.3%; 0 volunteers), and nausea (6 volunteers, 13.3%; 2 volunteers, 13.3%). The most common adverse events of all causes in the MAD cohort are summarized in Table 2. All adverse events resolved except for one case of moderate urticaria. This urticaria occurred in the declavatinib 6 mg bid group and was considered unrelated to the study treatment. Seven volunteers discontinued the trial due to adverse events: six volunteers discontinued the trial after taking deucravacitinib (2 mg bid: 1 volunteer, chest pain; 4 mg bid: 1 volunteer, rash; 6 mg bid: 2 volunteers, urticaria; 12 mg bid: 1 volunteer, tonsillitis; 12 mg qd: 1 volunteer, boil), and one volunteer discontinued the trial in the placebo group (decreased consciousness). [2] Compared with placebo, deucravacitinib increased the incidence of rash and acne and urticaria-like skin reactions, especially at the highest dose of 24 mg/day (12 mg bid dose group). The severity of skin rash/acne adverse events was mild or moderate and could be treated with topical treatment (corticosteroid cream for urticaria-like rash, benzoyl peroxide cream, clindamycin solution or chlorhexidine ointment for acne) as needed, and rarely led to discontinuation. [2]
White blood cell counts were monitored using standard automated cell counting methods, and major white blood cell populations were further counted using TBNK flow cytometry. The results showed that no abnormalities were observed in T cells, B cells, or natural killer (NK) cell subsets after deucravacitinib treatment (data not shown). [2]
No dose-related trends of any significant clinical laboratory abnormalities or electrocardiographic abnormalities (including ECG intervals exceeding the normal range) were observed at any stage of the study, nor were any effects of deucravacitinib on heart rate or body temperature observed. [2]

[1]. Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165. J Med Chem. 2019 Oct 24;62(20):8973-8995.

[2]. First-in-human study of deucravacitinib: A selective, potent, allosteric small-molecule inhibitor of tyrosine kinase 2. Clin Transl Sci. 2023 Jan;16(1):151-164.

Pharmacodynamics
Deucravacitinib is a tyrosine kinase 2 (TYK2) inhibitor that inhibits immune signaling pathways in inflammatory diseases such as plaque psoriasis. In clinical studies involving psoriasis patients, deucravacitinib reduced the expression of psoriasis-related genes in psoriatic skin in a dose-dependent manner, including genes regulated by the IL-23 pathway and type I interferon pathway. After 16 weeks of once-daily treatment, deucravacitinib reduced inflammatory markers such as IL-17A, IL-19, and β-defensin by 47% to 50%, 72%, and 81% to 84%, respectively. Deucravacitinib does not affect JAK2-dependent hematopoiesis. Small molecule JAK inhibitors have become a major breakthrough in the treatment of autoimmune diseases. Traditionally, isoenzyme-selective inhibitors of the JAK kinase family have primarily targeted their catalytically active sites, and discovering such inhibitors has been a significant challenge. Our strategy for achieving high selectivity for TYK2 is to target the TYK2 pseudokinase (JH2) domain. This paper reports on the later optimization work, including structure-guided design and water displacement strategy, which ultimately led to the discovery of BMS-986165 (11), a high-affinity JH2 ligand and a potent TYK2 allosteric inhibitor. In addition to unprecedented selectivity for JAK isozymes and kinases, compound 11 also exhibits excellent pharmacokinetic properties with very low pharmacokinetic defects and is effective in a variety of mouse models of autoimmune diseases. Based on these findings, compound 11 is distinct from other reported JAK inhibitors and has entered clinical development as the first oral autoimmune disease treatment targeting pseudokinases. [1]

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This randomized, double-blind, single-dose and multiple-escalation dose study evaluated the pharmacokinetics (PK), pharmacodynamics, and safety (NCT02534636) of the selective and potent tyrosine kinase 2 small molecule inhibitor deucravacitinib (Sotyktu™) in 100 healthy volunteers (75 in the active drug group and 25 in the placebo group). Deucravacitinib is rapidly absorbed with a half-life of 8–15 hours, and its accumulation is 1.4–1.9 times after multiple doses. In vitro studies have shown that deucravacitinib inhibits interleukin (IL)-12/IL-18-induced interferon (IFN)γ production in a dose- and concentration-dependent manner. In vivo studies have shown that, upon IFNα-2a stimulation, deucravacitinib inhibits lymphocyte count decline and the expression of 53 IFN-regulated genes in a dose-dependent manner. No serious adverse events (AEs) occurred; the overall incidence of AEs was similar in the deucravacitinib group (64%) and the placebo group (68%). In this first-in-human trial, deucravacitinib inhibited the IL-12/IL-23 and type I interferon pathways in healthy volunteers with favorable pharmacokinetics and safety. Deucravacitinib shows promise as an effective treatment for immune-mediated diseases, including Crohn's disease, psoriasis, psoriatic arthritis, and systemic lupus erythematosus. [2]

C20H23CLN8O3

461.91990685463

1609392-28-0

1609392-27-9

146048026

Typically exists as solids at room temperature

4

8

7

32

648

0

Cl.O=C(C1CC1)NC1=CC(=C(C(NC([2H])([2H])[2H])=O)N=N1)NC1C=CC=C(C2N=CN(C)N=2)C=1OC

BMS-986165 hydrochloride; Deucravacitinib hydrochloride; BMS-986165 hydrochloride; 95C5558CF4; UNII-95C5558CF4; 1609392-28-0; 3-Pyridazinecarboxamide, 6-((cyclopropylcarbonyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-, hydrochloride (1:1)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)