Table 1.

STAT3 inhibitors at various stages of pre-clinical and/or clinical testing for Asthma, IBD, cachexia and Fibrosis.

Inhibitor	Target	Preclinical/Clinical Model	Goals/Results	Ref.
Asthma
TyrA1	Jak	HDM-induced STAT3-mediated mice model of asthma	Blocked HDM-induced STAT3 activation and airway eosinophilia in mice	[14]
Vr588	Jak	HDM-induced STAT3-mediated mice model of asthma. Intra-nasal VR588 (1.5 and 50 mg/kg) vs oral 15 mg/kg PK. HDM extract (25 μg) intranasally 5 days/week for 3 weeks with multiple intranasal doses (1.5 to7.5 mg/kg) given 1 hour prior to each HDM exposure; a separate group administered a VR588 7.5 mg/kg intranasal dose only during the last week of HDM treatment (n = 8). Comparison was made with oral tofacitinib (15 mg/kg) and fluticasone propionate (1.5 mg/kg).	VR588 resulted in significant reduction of AHR at least comparable to that achieved by FP. All VR588 doses significantly reduced BAL total cell count with a variety of doses inhibiting macrophage, neutrophil, lymphocyte and eosinophil counts. VR588 attenuated the induction of numerous cytokines (IL-4, IL-5, IL-17) compared with saline control, As well as HDM induced pSTAT3	[27,28]
Mepolizumab	IL5 antagonist	Rhinovirus-induced Allergic Asthma Exacerbations; multicenter, double-blind, placebo-controlled DREAM trial	Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma	[24,25,26,27]
JTE-013	S1PR2	Dinitrophenyl (DNP) induced asthma model	Suppressed STAT3 activation, reduced chemokine secretion and prevented early T-cell recruitment in mice lungs after antigen challenge	[29]
STAT1/3 dODN	STAT1/3	DM-induced STAT3-mediated mice model of asthma	reduce airway inflammation and AHR in lungs of mice challenged with HDM	[30]
C188-9	STAT3	HDM-induced STAT3-mediated mice model of asthma	Normalization of IL-4, IL-5, IL-13, and IL-17A cytokine levels, as well as prevention of HDM-induced increases in Th2 cells, Th17 cells, and IL-4- and IL-17A-producing non-T cells	[22]
IBD
Tocilizumab (MRA)	anti-IL6R MAb	Phase II Clinical: 36 patients with active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] >150) randomly assigned to receive IV infusion of placebo/MRA/alternate MRA-placebo 12 weeks at 8 mg/kg	80% of the patients (8 of 10) given biweekly MRA had a clinical response as compared with 31% of the placebo-treated patients (4 of 13; P = 0.019).	[31]
TJ301 ( Olamkicept )	IL6R antagonist	Safety and Efficacy of intravenous TJ301 in Participants With Active Ulcerative Colitis	Ongoing Study	[32]
C326	IL-6 Inhibitory Avimer protein	Placebo-Controlled, Phase 1, Single and Multiple IV Dose Escalation Study of the Safety, in Adults With Crohn’s Disease	Pharmacokinetics, Pharmacodynamics, and Immunogenicity of C326 in Adults With Crohn’s Disease	[33]
Vidofludimus	IL17A, IL17F, and IFN-γ	Open-label uncontrolled entrance study of patients with IBD conducted at 13 study centers in Germany, Bulgaria and Romania	12 weeks treatment phase; 8 out of 14 (57.1%) patients with CD and 6 out of 12 (50.0%) patients with UC were in steroid-free remission (complete responders). Another 4 (28.6%) patients in CD and 5 (41.7%) patients in UC were partial responders. Vidofludimus was well tolerated, with no drug-related serious adverse events.	[34]
Ustekinumab	anti-IL12p40 MAb	Double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohn’s disease (Population 1). Open label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2).	In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (p 0.02), respectively at weeks 4 and 6, and 49% and 40% (p 0.34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (p < 0.05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively.	[35,36]
Janex-1	Jak3	Murine TNBS-induced colitis model	Attenuation of disease manifestations	[37,38,39]
Tofacitinib GLPG0634/GS-6034/CP-690550	Jak3	Phase II Clinical: moderate-to-severe UC	inducing clinical responses and remissions and has been FDA approved as the only nonsteroidal oral treatment that induces remission for moderate-to-severe UC	[40,41]
Filgotinib	Jak1	Phase II Clinical: Crohn’s Disease		[42,43]
Upadacitinib (ABT-494, AbbVie)	Jak1	Phase II Clinical: Crohn’s Disease, Adult patients with active CD, with a CDAI 220-450, an average daily liquid/soft stool frequency (SF) ≥2.5 or daily abdominal pain (AP) score ≥2.0, and Simplified Endoscopic Score for CD (SES-CD) ≥6 (or ≥4 for those with isolated ileal disease), were randomized 1:1:1:1:1:1 to doubleblind induction therapy with placebo (PBO) or ABT-494 at 3, 6, 12, 24 mg twice daily (BID) or 24 mg once daily (QD) for 16 weeks, followed by blinded extension therapy for 36 weeks	This dose-ranging study demonstrated endoscopic improvement and clinical benefit of ABT-494 as induction therapy in patients with moderate-to-severe refractory CD, and a safety profile as expected with a JAK inhibitor in this population.	[44]
C188-9	STAT3	Murine models of DSS-induced UC and TNBS-induced CD	All manifestations of DSS-induced UC and TNBS-induced CD in mice were prevented by C188-9 treatment. C188-9 treatment also induced increased apoptosis of pathogenic CD4+ T-cells, and reduced colon levels of IL-17-positive cells in both models.	[45,46]
Cachexia
STAT3 SH2 domain mimetic peptide (SIP)	STAT3	C2C12 cell culture model of muscle differentiation	48h treatment resulted in modest myofiber hypertrophy and prevented IL-6-induced fiber atrophy	[47]
C188-9	STAT3	CDK cachexia mouse model	C188-9 treatment antagonized catabolic signaling by decreasing myostatin expression and the activation of its downstream signaling mediators, p-Smad2 and p-Smad3. In addition, C188-9 increased muscle mass in tumor-bearing mice by augmenting muscle protein synthesis and suppressing protein degradation	[48]
AR-42	HDAC inhibitor	C26 cachexia mouse model	anabolic androgen therapy in combination with HDAC Inhibitor AR-42 was shown to block STAT3 mediated muscle atrophy.	[49]
Ruxolitinib (INCB018424)	Jak1/2, STAT3	Incyte, 127 patient, randomized phase II, Cancer associated weight loss trial focused on exocrinemetastatic pancreas cancer patients who had failed first-line chemotherapy, who typically suffer an inexorable decline in weight. Patients received capecitabine and, in addition, were randomly assigned to ruxolitinib versus placebo	The trial’s primary endpoint focused on survival, justified based on the negative prognostic effect of cancer-associated weight loss [11]. The hazard ratio for survival was 0.79 (one-sided P ¼ 0.12), but in an a priori subgroup analysis which was intended to identify patients most likely to benefit from JAK inhibition, the hazard ratio for survival was 0.47 (one-sided P ¼ 0.005). In this same subgroup, the 6-month survival rate with ruxolitinib was 42% compared to 11% with placebo. Importantly, ruxolitinib-treated patients manifested a significant improvement in body weight compared with placebo. Ruxolitinib was also relatively well tolerated	[50,51]
Fibrosis
JSI-124	Jak2	bleomycin-induced lung fibrosis in rats	In rats administered JSI-124, a Jak2 inhibitor that targets STAT3 indirectly, several markers of bleomycin-induced lung fibrosis were reduced	[52,53]
cucurbitacin-B	Jak2	carbon tetrachloride (CCl4) model of fibrosis	Decreased fibrosis and diminished levels of hydroxyproline in liver tissue as well as expression of collagen-1α, α-SMA and TGF-β	[54]
Pacritinib (SB1518)	Jak2	Myelofobrosis, AML (Combined With Decitabine/Cytarabine)	Active drug in myelofibrosis. Going in the AML patients for safety efficacy as a STAT3 inhibitor in combination with Decitabine/Cytarabine	[55,56]
Ruxolitinib (INCB018424)	Jak1/2	COMFORT (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy)-I Trial	Ruxolitinib provided significant reductions in splenomegaly, improvements in myelofibrosis (MF)-related symptoms including cachexia, and a survival advantage relative to placebo in patients with intermediate-2 or high-risk MF. Ruxolitinib treatment was associated with increased weight (mean change: 3.9 kg vs. −1.9 kg), total cholesterol (mean percentage change: 26.4% vs. −3.3%), and albumin levels (mean percentage change: 5.8% vs. −1.7%) at week 24; sustained improvements were observed with longer-term ruxolitinib therapy.	[57,58,59]
S3I-201	STAT3	preclinical animal mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction	Attenuated interstitial fibrosis and showed a fibrotic suppression profile similar to other inhibitors	[60,61]
C188-9	STAT3	Bleomycin-induced lung fibrosis Bleomycin-induced and (Tsk-1) models of scleroderma hepatocyte-specific Pten knockout (HepPten-) mouse model of nonalcoholic steatohepatitis (NASH),	C188-9 ameliorated the development of pulmonary fibrosis, reduced expression of genes associated with type II alveolar epithelial cell (AEC) injury and fibrosis, blocked myofibroblast differentiation. Reduced fibrosis in both models of scleroderma as measured by loss of collagen accumulation and decrease in dermal and hypodermal thickness Reduced liver steatosis and hepatic fibrosis in addition to blocking progression of hepatocellular carcinoma	[62,63,64,65]

S1PR2: sphingosine-1 phosphate (S1P) receptor 2 (R2), NA: Not available, MAb: Monoclonal Antibody, SM: small molecule, pY: STAT3 phosphorylation at Tyr-705.