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].

---

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].

---

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].

---

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
Following oral administration, deucravacitinib plasma Cmax and AUC increased proportionally over a dose range from 3 mg to 36 mg (0.5 to 6 times the approved recommended dosage) in healthy subjects. The steady state Cmax and AUC24 of deucravacitinib following administration of 6 mg once daily were 45 ng/mL and 473 ng x hr/mL, respectively. The steady state Cmax and AUC24 of the active deucravacitinib metabolite, BMT-153261, following administration of 6 mg once daily were 5 ng/mL and 95 ng x hr/mL, respectively. The absolute oral bioavailability of deucravacitinib was 99% and the median Tmax ranged from two to three hours. A high-fat, high-calorie meal decreased Cmax and AUC of deucravacitinib by 24% and 11%, respectively, and prolonged Tmax by one hour; however, this has clinically significant effects on drug absorption and exposure.
After a single dose of radiolabeled deucravacitinib, approximately 13% and 26% of the dose was recovered as unchanged in urine and feces, respectively. Approximately 6% and 12% of the dose was detected as BMT-153261 in urine and feces, respectively.
The volume of distribution of deucravacitinib at steady state is 140 L.
The renal clearance of deucravacitinib ranged from 27 to 54 mL/minute.

---

Metabolism / Metabolites
Deucravacitinib undergoes N-demethylation mediated by cytochrome P-450 (CYP) 1A2 to form major metabolite BMT-153261, which has a comparable pharmacological activity to the parent drug. However, the circulating exposure of BMT-153261 accounts for approximately 20% of the systemic exposure of the total drug-related components. Deucravacitinib is also metabolized by CYP2B6, CYP2D6, carboxylesterase (CES) 2, and uridine glucuronyl transferase (UGT) 1A9.

---

Biological Half-Life
The terminal half-life of deucravacitinib was 10 hours.

---

Triazole 11/Deucravacitinib (BMS-986165) Shows Minimal Profiling Liabilities, Excellent PK Properties, and Is Highly Efficacious in Inflammatory and Autoimmune Disease Models [1]
Having demonstrated excellent potency and functional selectivity for inhibition of TYK2-dependent responses, 11/Deucravacitinib (BMS-986165) was further profiled in vitro and showed minimal liabilities and acceptable PK properties for further advancement (Table 7). Incubation in liver microsomes shows excellent stability (T1/2 > 120 min) across multiple species including human, mouse, rat, monkey, dog, and rabbit. Good permeability is also observed in a Caco-2 assay with moderate efflux (apical-to-basal Pc = 73 nm/s; basal to apical Pc = 740 nm/s; efflux ratio ∼10). Assessment of the potential for drug–drug interactions (DDI) indicates a low overall risk, as no significant inhibition of multiple cytochrome P450 (CYP) isozymes (1A2, 2C9, 2C19, 2D6, and 3A4) or induction of CYP3A4 is observed up to the highest concentration tested (40 μM). Testing of 11 in the hERG potassium channel patch clamp assay gives a low percent inhibition (26 ± 11% at 10 μM), suggesting a low potential for QTc prolongation-associated cardiovascular risk. Protein binding is in the moderate range (12–15% free) across species including human, monkey, and mouse. Aqueous solubility of the crystalline free base form of 11 is low at 5.2 μg/mL but was deemed acceptable for advancement into preclinical studies. Good overall PK parameters were observed with 11 in preclinical studies across multiple species (Table 8). Consistent with the observed low rate of metabolism in the microsomal assays (T1/2 > 120 min), 11 affords low to modest in vivo clearance rates in mouse, dog, and monkey of 13.2, 6.8, and 4.8 mL min–1 kg–1, respectively. Low volume of distribution (Vss) is also observed in the 2–3 L/kg range with moderate half-lives of ∼4–5 h across species. When administered orally at 10 mg/kg, 11 is well absorbed with excellent exposures and high bioavailability (%F > 85) in mouse, dog, and monkey. Circulating primary amide metabolite formation from N-dealkylation of the deuteromethyl amide of 11 was near the lower limits of detection (<2 nM) in these studies, consistent with the effective blocking of this metabolic pathway by deuteration as previously reported within the series.

---

Pharmacokinetic in healthy volunteers [2]
After administration, Deucravacitinib (BMS-986165) was rapidly absorbed and exhibited an apparent elimination t 1/2 of 7.9–15.0 h following a single dose, and a mean effective t 1/2 of 7.5–13.1 h after multiple dosing (Figure 1, Table 1). The Cmax and AUCINF showed a greater than proportional increase with ascending doses following a single dose of deucravacitinib (up to 10 mg in the SAD cohort) but showed an apparent dose proportionality at doses ≥10 mg. A similar PK profile was seen following multiple doses in the MAD cohort, with dose proportionality at doses ≥4 mg b.i.d. Modest accumulation (1.4–1.9‐fold) was observed after multiple dosing, with steady‐state reached by day 5, the first day on which Cmin samples were collected. Urinary recovery of unchanged deucravacitinib was assessed in the SAD cohort only, and ranged from 10% to 15% across all doses; renal clearance of deucravacitinib ranged from 27.5 to 54.2 ml/min across the dose range.

Hepatotoxicity
In the preregistration clinical trials of deucravacitinib that included data on 1519 subjects, only 1.8% of patients had serum ALT or AST elevations above 5 times ULN, none of which were considered likely due to drug induced liver injury, with myositis accounting for many of the elevations, and underlying alcoholic or nonalcoholic fatty liver disease accounting for a few. Elevations of ALT levels above 3 times the ULN arose in 1.1% to 1.3% of recipients of deucravacitinib in a 24 week trial compared to 1.2% of placebo recipients. While there were no instances of reactivation of hepatitis B in patients receiving deucravacitinib, patients with preexisting HBsAg in serum were excluded from enrollment and most treatment courses were limited in duration. Since its approval and more widespread clinical use, there have been no further reports of clinically apparent liver injury attributed to deucravacitinib, but it has been available for a limited time only.
Likelihood score: E (suspected but unproven cause of clinically apparent liver injury including reactivation of hepatitis B).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of deucravacitinib during breastfeeding. Because it is more than 80% bound to plasma proteins, the amount in milk is likely to be low. However, it is well absorbed orally. If deucravacitinib is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◈ What is deucravacitinib?
Deucravacitinib is a medication that has been approved for the treatment of moderate-to-severe plaque psoriasis. MotherToBaby has a fact sheet on psoriasis & psoriatic arthritis at: https://mothertobaby.org/fact-sheets/psoriasis-and-pregnancy/. A brand name for deucravacitinib is SOTYKTU™.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take deucravacitinib. Can it make it harder for me to get pregnant?
Studies have not been done to see if deucravacitinib can make it harder to get pregnant.
◈ Does taking deucravacitinib increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if deucravacitinib increases the chance for miscarriage.
◈ Does taking deucravacitinib increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Human pregnancy studies have not been with deucravacitinib. Experimental animal studies reported by the manufacturer did not find an increased chance of birth defects.
◈ Does taking deucravacitinib in pregnancy increase the chance of other pregnancy related problems?
Studies have not been done to see if deucravacitinib increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ Does taking deucravacitinib in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if deucravacitinib can cause behavior or learning issues for the child.
◈ Breastfeeding while taking deucravacitinib:
Deucravacitinib has not been studied for use while breastfeeding. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes deucravacitinib, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects in a partner’s pregnancy?
Studies have not been done to see if deucravacitinib could affect male fertility or increase the chance of birth defects in a partner’s pregnancy. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

---

Protein Binding
Protein binding of deucravacitinib was 82 to 90% and the blood-to-plasma concentration ratio was 1.26.

---

Toxicity Summary
No clinical data is available for experience with deucravacitinib overdosage. If overdosage occurs in any patients, it is recommended to contact the Poison Help line for additional management of the condition according to the drug overdosage protocol. The elimination of deucravacitinib by treatment with hemodialysis was small in extent, up to 5.4% of the dosage per dialysis therapy, and therefore, limiting the use of hemodialysis in the treatment of overdosage or intoxication with deucravacitinib.
Various studies using rate models have demonstrated no carcinogenicity was observed in male or female rats that administered deucravacitinib orally at doses up to 15 mg/kg/day, which is 51-fold higher than the MRHD as per AUC comparison. In rats of the female gender, deucravacitinib had no effects on parameters of reproduction such as mating, fertility, or early development of the embryo at orally administered doses up to 50 mg/kg/day which is 171-fold higher than the MRHD, according to the comparison of AUC. In the male rat, deucravacitinib had no effects on mating, sperm morphology, fertility, or early embryonic parameters of their offspring at orally administered doses up to 50 mg/kg/day, which is 224 times higher than the MRHD according to a comparison of AUC.

---

In the SAD cohort, AEs were reported in 11 volunteers (36.7%) who received deucravacitinib and four volunteers (40%) who received placebo; the most frequently reported AE by preferred term was headache (deucravacitinib: 5 volunteers, 16.7%; placebo: 2 volunteers, 20.0%). A total of seven (23.3%) gastrointestinal disorder AEs (system order class) were reported in volunteers receiving deucravacitinib versus no volunteers in the placebo group, with the most common being dyspepsia reported in three volunteers (10%). All AEs were mild in severity, with the exception of one event of presyncope of moderate severity in the placebo group. The most common all‐cause AEs in the SAD cohort are summarized in Table 2.[2]
In the MAD cohort, all AEs were mild to moderate in severity, and the overall frequency of AEs was similar in the deucravacitinib (37 volunteers, 82%) and placebo (13 volunteers, 87%) groups. For the deucravacitinib and placebo groups, respectively, the most frequently reported AEs by preferred term 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 all‐cause AEs in the MAD cohort are summarized in Table 2. All AEs resolved except for one case of urticaria of moderate severity, which occurred in the deucravacitinib 6 mg b.i.d. group, and was considered unrelated to study treatment. A total of seven volunteers discontinued due to AEs: six following administration of deucravacitinib (2 mg b.i.d.: 1 volunteer, chest pain; 4 mg b.i.d.: 1 volunteer, rash; 6 mg b.i.d.: 2 volunteers, urticaria; 12 mg b.i.d.: 1 volunteer, tonsillitis; 12 mg q.d.: 1 volunteer, furuncle) and one volunteer in the placebo group (decreased consciousness).[2]
Deucravacitinib was associated with an increased incidence of skin rashes and acne‐ and urticaria‐like skin reactions versus placebo, particularly at the highest dosage of 24 mg/day (12 mg b.i.d. dose panel). Skin rash/acne AEs were of mild or moderate severity, responded well to topical treatment (corticosteroid cream for urticaria‐like rash and benzoyl peroxide cream, clindamycin solution, or chlorhexidine ointment for acne) if required, and rarely led to discontinuation.[2]
White blood cell counts were monitored by a standard automated cell count and further enumeration of major white blood cell populations using TBNK flow cytometry identified no abnormalities in T, B, or natural killer (NK) cell subsets following exposure to deucravacitinib (data not shown).[2]
There were no dose‐related trends in the occurrence of any clinical laboratory marked abnormalities or ECG abnormalities, including out‐of‐range ECG intervals, in any part of the study, and no effect of deucravacitinib on heart rate or body temperature was 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 works to suppress the immune signaling pathways in inflammatory disorders, such as plaque psoriasis. In clinical studies comprising patients with psoriasis, deucravacitinib reduced psoriasis-associated gene expression in psoriatic skin in a dose dependent manner, including reductions in IL-23-pathway and type I IFN pathway regulated genes. Following 16 weeks of once-daily treatment, deucravacitinib reduced inflammatory markers such as IL-17A, IL-19 and beta-defensin by 47 to 50%, 72%, and 81 to 84%, respectively. Deucravacitinib does not affect with JAK2-dependent hematopoietic functions.

---

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. 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]

---

This randomized, double-blind, single- and multiple-ascending dose study assessed the pharmacokinetics (PKs), pharmacodynamics, and safety of deucravacitinib (Sotyktu™), a selective and potent small-molecule inhibitor of tyrosine kinase 2, in 100 (75 active, 25 placebo) healthy volunteers (NCT02534636). Deucravacitinib was rapidly absorbed, with a half-life of 8-15 h, and 1.4-1.9-fold accumulation after multiple dosing. Deucravacitinib inhibited interleukin (IL)-12/IL-18-induced interferon (IFN)γ production ex vivo in a dose- and concentration-dependent manner. Following in vivo challenge with IFNα-2a, deucravacitinib demonstrated dose-dependent inhibition of lymphocyte count decreases and expression of 53 IFN-regulated genes. There were no serious adverse events (AEs); the overall frequency of AEs was similar in the deucravacitinib (64%) and placebo (68%) groups. In this first-in-human study, deucravacitinib inhibited IL-12/IL-23 and type I IFN pathways in healthy volunteers, with favorable PK and safety profiles. Deucravacitinib is a promising therapeutic option 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

Typically exists as solids at room temperature

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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