CD200 is an anti-inflammatory protein that facilitates signal transduction through its receptor, CD200R, in cells, resulting in immune response suppression. This includes reducing M1-like macrophages, enhancing M2-like macrophages, inhibiting NK cell cytotoxicity, and downregulating CTL responses. Activation of CD200R has been found to modulate dendritic cells, leading to the induction or enhancement of Treg cells expressing Foxp3. However, the precise mechanisms behind this process are still unclear. Our previous study demonstrated that B cells in Peyer’s patches can induce Treg cells, so-called Treg-of-B (P) cells, through STAT6 phosphorylation. This study aimed to investigate the role of CD200 in Treg-of-B (P) cell generation. To clarify the mechanisms, we used wild-type, STAT6 deficient, and IL-24 deficient T cells to generate Treg-of-B (P) cells, and antagonist antibodies (anti-CD200 and anti-IL-20RB), an agonist anti-CD200R antibody, CD39 inhibitors (ARL67156 and POM-1), a STAT6 inhibitor (AS1517499), and soluble IL-20RB were also applied. Our findings revealed that Peyer’s patch B cells expressed CD200 to activate the CD200R on T cells and initiate the process of Treg-of-B (P) cells generation. CD200 and CD200R interaction triggers the phosphorylation of STAT6, which regulated the expression of CD200R, CD39, and IL-24 in T cells. CD39 regulated the expression of IL-24, which sustained the expression of CD223 and IL-10 and maintained the cell viability. In summary, the generation of Treg-of-B (P) cells by Peyer’s patch B cells was through the CD200R-STAT6-CD39-IL-24 axis pathway.

01 Jan 2024·International journal of biological macromolecules

Chitosan-coated artesunate protects against ulcerative colitis via STAT6-mediated macrophage M2 polarization and intestinal barrier protection

Article

Author: Yu, Jie ; Liu, Mingjiang ; Gu, Wenyi ; Liu, Xiaopan ; Wei, Simin ; Bo, Ruonan ; Tao, Ya ; Huang, Yinmo ; Wang, Peijia ; Li, Jingui ; Xu, Lei

Oral delivery of chitosan-coated artesunate (CPA) has been proven to be effective at preventing ulcerative colitis (UC) in mice. However, the anti-inflammatory mechanism is not fully understood. STAT6 is a key transcription factor that promotes anti-inflammatory effects by inducing M2 and Th2 dominant phenotypes, therefore we hypothesized STAT6 might play a key role in the process. To prove it, a STAT6 gene knockout macrophage cell line (STAT6^-/- RAW264.7, by CRISPR/Cas9 method), and its corresponding Caco-2/RAW264.7 co-culture system combined with the STAT6 inhibitor (AS1517499, AS) in a mouse UC model were established and studied. The results showed that CPA remarkably suppressed the activation of TLR-4/NF-κB pathway and the mRNA levels of proinflammatory cytokines, while increased the IL-10 levels in RAW264.7. This effect of CPA contributed to the protection of the ZO-1 in Caco-2 which was disrupted upon the stimulation to macrophages. Simultaneously, CPA reduced the expression of CD86 but increase the expression of CD206 and p-STAT6 in LPS-stimulated RAW264.7 cells. However, above alterations were not obvious as in STAT6^-/- RAW264.7 and its co-culture system, suggesting STAT6 plays a key role. Furthermore, CPA treatment significantly inhibited TLR-4/NF-κB activation, intestinal macrophage M1 polarization and mucosal barrier injury induced by DSS while promoted STAT6 phosphorylation in the UC mouse model, but this effect was also prominently counteracted by AS. Therefore, our data indicate that STAT6 is a major regulator in the balance of M1/M2 polarization, intestinal barrier integrity and then anti-colitis effects of CPA. These findings broaden our understanding of how CPA fights against UC and imply an alternative treatment strategy for UC via this pathway.

01 Jun 2023·Journal of biochemical and molecular toxicology

Sunitinib suppresses M2 polarization of macrophages in tumor microenvironment to regulate hepatocellular carcinoma progression

Article

Author: Guo, Li ; Kong, Yun

Abstract:

This work aimed to investigate the role and mechanism of Sunitinib (Sun) in suppressing M2 polarization of macrophages in tumor microenvironment (TME). IL‐4 was applied to induce the M2 polarization of RAW264.7 cells, followed by treatment with Sun at 50 and 100 nM. Flow cytometry (FCM) was conducted to detect the proportion of F4/80 + CD206 + cells. Enzyme‐linked immunosorbent assay (ELISA) was performed to measure the levels of IL‐10, Arg‐1 and VEGF. Immunofluorescence (IF) staining was carried out to detect the expression of CD206 and Arg‐1. Besides, western‐Blot (WB) assay was performed to measure the levels of p‐JAK1 and p‐STAT6 proteins. After polarization, the macrophage culture medium was employed to culture hepatocellular carcinoma (HCC) Hca‐F cells. Thereafter, Transwell assays were conducted to examine cell invasion and migration, whereas plate clone formation assay was carried out to detect the clone forming capacity. In further experiments, cells were treated with the STAT6 inhibitor, or STAT6 inhibitor + Sun. Then, the polarization levels of RAW264.7 cells were detected. Moreover, this study established the xenograft tumor mouse model. Later, CD206 and Ki67 expression, IL‐10, Arg‐1 and VEGF expression levels in tissues, and p‐JAK1 and p‐STAT6 protein levels were detected by histochemical staining. Sun suppressed the M2 polarization of RAW264.7 cells. Compared with IL‐4 treatment, the proportion of F4/80 + CD206 + cells decreased. Meanwhile, the levels of IL‐10, Arg‐1 and VEGF were downregulated, and the phosphorylation level of JAK1‐STAT6 signaling was suppressed. After being cocultured with Hca‐F, the malignant behaviors of HCC cells were suppressed after Sun treatment. Similarly, STAT6 inhibitor treatment suppressed the M2 polarization, while the combined application of Sun did not further restrain the polarization level. In the mouse model, Sun suppressed the expression of CD206 and Ki67, simultaneously inhibiting the polarization of JAK1‐STAT6 signaling. Sunitinib can suppress the M2 polarization of macrophages to exert the anti‐HCC effect, which is its another anticancer mechanism

News (Medical) associated with STAT6 inhibitor(C&C Research)

10 Jun 2025

·www.prnewswire.com

DeepCure Announces DC-15442 as Development Candidate, an Oral STAT6 Inhibitor with 100% in vivo inhibition of pSTAT6 and comparable efficacy to dupilumab across disease models

DC-15442 is a potent small molecule STAT6 inhibitor, which is not a degrader or prodrug, being advanced as a safe dupilumab-in-a-pill alternative for patients BOSTON, June 10, 2025 /PRNewswire/ -- DeepCure, an immunology therapeutics company leveraging artificial intelligence (AI) to rapidly advance novel small molecule drugs, today announced the nomination of DC-15442 as its second development candidate. DC-15442 is a potent, selective, oral STAT6 inhibitor designed to replicate the safety as well as the efficacy of dupilumab, without requiring regular subcutaneous injections. Dupilumab is FDA-approved for multiple indications driven by Type 2 inflammation, including atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria, eosinophilic esophagitis, and prurigo nodularis. DeepCure designed DC-15442 to meet the demand for an oral alternative that is not only equally effective as dupilumab, but also has excellent safety, given that many patients are children and reproductive-aged adults with chronic, non-life-threatening conditions. DC-15442 inhibits the same IL-4/IL-13 signaling pathway as dupilumab by blocking the interaction between unphosphorylated STAT6 (uSTAT6) and the IL-4Ra receptor, and by preventing nuclear translocation and dimerization of phosphorylated STAT6 (pSTAT6). Importantly, like dupilumab, DC-15442 does not degrade STAT6 proteins or impair uSTAT6 non-inflammatory functions. Therefore, DC-15442 does not have the on-target safety concerns of potential therapies based on STAT6 degradation. In preclinical evaluations, DC-15442 achieved nearly 100% inhibition of pSTAT6 in the acute ovalbumin (OVA) allergy models, which outperforms IL-4Ra antibodies and other STAT6 inhibitors. In direct comparisons using the MC903 atopic dermatitis model, DC-15442 matched dupilumab's effectiveness, significantly reducing serum IgE levels to those seen in healthy controls. Additionally, DC-15442 has a dramatic effect on lung function in asthma models, restoring lung function to almost the same levels as healthy controls, with an effect superior to a leading JAK inhibitor (upadacitinib) and dexamethasone. The development candidate also exhibits outstanding selectivity, showing no off-target activity across extensive screening panels - including 102 SH2 domain proteins, 468 kinases, and 78 assays targeting clinical adverse drug reaction-associated proteins. Preliminary in vivo safety assessments confirmed outstanding tolerability, with no observed adverse effects, underscoring its suitability for chronic use. In addition, DC-15442 is not a degrader, and therefore it does not have the potential toxicity concerns of PROTACs. "We are extremely pleased that, in addition to excellent efficacy, DC-15442 demonstrates a very clean safety profile," said Kfir Schreiber, CEO & Co-Founder, DeepCure. "Many of the patients who will consider an oral STAT6 inhibitor will need to have chronic treatment for non-life-threatening conditions, so safety is paramount. As a selective, oral inhibitor that replicates dupilumab's proven mechanism without the target and modality risks associated with protein degradation, DC-15442 may expand the treated population and transform patient quality of life." About DeepCure DeepCure was founded by researchers at MIT to accelerate breakthrough therapies using artificial intelligence (AI) and advanced physics simulations to innovate small molecule discovery. The company is based in Boston, MA, and its engineers, chemists, and biologists collaborate on hard problems to find solutions that will have an enormous impact on patient health. For more information, visit . Contact [email protected] SOURCE DeepCure WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Drug ApprovalClinical Result

20 Jul 2023

·www.fiercebiotech.com

Sanofi pays $125M to go after undruggable inflammatory target with Recludix's preclinical program

“In an era where a lot of financings are down rounds or very diluted, this was a very attractive option for us," Recludix's CEO Nancy Whiting said of the Sanofi deal. Sanofi is paying Recludix Pharma $125 million and offering up more than $1.2 billion in biobucks for a pact taking aim at multiple immunological and inflammatory indications. “It's a great deal for Recludix; we're really thrilled,” Nancy Whiting—who joined as the biotech’s first CEO in 2021 after more than 14 years at Seagen—told Fierce Biotech in an interview. “It's a really high-value deal and I think it'll be transformational for Recludix.” The agreement centers around Recludix’s preclinical STAT6 inhibitor. The first-in-class oral small-molecule drug works on the SH2 domain, which was historically considered an undruggable target. Now, Recludix thinks it has cracked the code by blocking STAT6, a key nodal transcription factor that selectively mediates downstream IL-4 and IL-13 signaling, which drives type 2 inflammatory diseases like asthma, atopic dermatitis and allergies. Sanofi has signed on to help develop and potentially commercialize the California biotech’s program, with expectations of entering the clinic in 2025. "Recludix’s approach to targeting STAT6 has significant potential for a number of I&I diseases, especially where a precisely tailored oral therapy could best fit within the patient’s needs at various stages of disease," Frank Nestle, M.D., Sanofi’s chief scientific officer and global head of research, said in a July 20 release. Under the terms of the deal, Recludix will advance STAT6 inhibitors from preclinical research until the start of phase 2 trials, when Sanofi will take over clinical development. The French Big Pharma will also be responsible for commercialization activities and have global rights for any small-molecule STAT6 inhibitors that make it to market. In addition to the near-term $125 million payment, Sanofi could potentially dole out more than $1.2 billion for development, regulatory and sales milestones alongside royalties on possible future sales. Sanofi is also giving Recludix the option to participate in U.S. profit or loss share. “An option for Recludix to participate in a 50/50 U.S. profit share is really huge,” Whiting said, citing the ability for the biotech to participate in the development and economics of the drug in a meaningful way. “This deal really helps validate that the work that we've done and the steps forward in the science we've made are really significant,” the CEO added. “In an era where a lot of financings are down rounds or very diluted, this was a very attractive option for us to bring in some non-dilutive capital, help continue to push this program forward and make sure it has absolutely everything it needs to be successful.”

License out/inExecutive ChangePhase 2

20 Jul 2023

·firstwordpharma.com

Sanofi partners with Recludix to develop oral STAT6 inhibitor

Sanofi signed a strategic collaboration with Recludix Pharma to develop oral small-molecule STAT6 inhibitors for patients with immunological and inflammatory diseases, the latter company said Thursday. The deal represents the second early-stage agreement for Sanofi this week, having unveiled a partnership on Monday with Scribe Therapeutics.Under the latest collaboration, Sanofi will have global rights to small-molecule STAT6 inhibitors, with Recludix advancing them from preclinical research and development through to the start of Phase II studies. The French drugmaker will subsequently assume development and commercialisation responsibilities, with Recludix having an option to participate in US profit/loss share.Recludix noted that inhibiting STAT6 - a key nodal transcription factor that selectively mediates downstream signalling of IL-4 and IL-13 – offers the potential to treat patients with multiple Type 2 inflammatory dermatological and respiratory diseases. "Recludix's approach to targeting STAT6 has significant potential…especially where a precisely tailored oral therapy could best fit within the patient's needs at various stages of disease," remarked Frank Nestle, Sanofi's global head of research.As part of the agreement, Sanofi will make near-term payments of $125 million, with Recludix eligible for more than $1.2 billion in potential milestones, as well as up to double-digit sales royalties.

License out/inPhase 2

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	United States	XtalPi, Inc.	18 Dec 2023
Inflammation	Preclinical	South Korea	C&C Research Laboratories	18 Dec 2023

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