Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available RORγt inverse agonist

Shibata, Akira; Uga, Keiko; Sato, Takayuki; Sagara, Masaki; Igaki, Keiko; Nakamura, Yoshiki; Ochida, Atsuko; Kono, Mitsunori; Shirai, Junya; Yamamoto, Satoshi; Yamasaki, Masashi; Tsuchimori, Noboru

doi:10.1016/j.bcp.2018.01.023

Cited by 28 publications

(24 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to targeting downstream effectors of Th17 pathways, the primary transcriptional regulator RORγt could be a promising therapeutic target. Several RORγt antagonists are used in ongoing clinical trials, such as GSK805 and TAK-828F, which both have shown prospective efficacy in preclinical models and animal models of inflammatory diseases ( 125 , 126 ). However, several questions remain about RORγt antagonism, including potential mechanisms of action, key target cells and effects on the homeostatic balance within Th17 cells and Treg cells ( 127 ).…”

Section: Therapeutic Implications Of Apmentioning

confidence: 99%

Role of Interleukin-17 in Acute Pancreatitis

Chen

Liu

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.

show abstract

Section: Therapeutic Implications Of Apmentioning

confidence: 99%

Role of Interleukin-17 in Acute Pancreatitis

Chen

Liu

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Several molecules targeting RORγt have been discovered and tested in murine models: digoxin, urosolic acid, and SR1001 reduce EAE severity (83)(84)(85); BI119 abrogates experimental colitis (86); SR2211 and JNJ-54271074 have therapeutic effect on experimental arthritis (87,88); TMP778 and S18-000003 show efficacy in a psoriasis-like skin inflammation model (89,90). In addition, other RORγt inverse agonists have been discovered (carbazole carboxamides, MG2778, TAK-828F, 6-substituted quinolines, A213) and tested as negative regulators of Th17 response (Table 1) (91)(92)(93)(94)(95)(96).…”

Section: Therapeutic Approaches Targeting Transcriptional Regulators mentioning

confidence: 99%

Transcriptional Regulators of T Helper 17 Cell Differentiation in Health and Autoimmune Diseases

2020

View full text Add to dashboard Cite

T helper (Th) 17 cells are a subtype of CD4 T lymphocytes characterized by the expression of retinoic acid-receptor (RAR)-related orphan receptor (ROR)γt transcription factor, encoded by gene Rorc. These cells are implicated in the pathology of autoimmune inflammatory disorders as well as in the clearance of extracellular infections. The main function of Th17 cells is the production of cytokine called interleukin (IL)-17A. This review highlights recent advances in mechanisms regulating transcription of IL-17A. In particular, we described the lineage defining transcription factor RORγt and other factors that regulate transcription of Il17a or Rorc by interacting with RORγt or by binding their specific DNA regions, which may positively or negatively influence their expression. Moreover, we reported the eventual involvement of those factors in Th17-related diseases, such as multiple sclerosis, rheumatoid arthritis, psoriasis, and Crohn's disease, characterized by an exaggerated Th17 response. Finally, we discussed the potential new therapeutic approaches for Th17-related diseases targeting these transcription factors. The wide knowledge of transcriptional regulators of Th17 cells is crucial for the better understanding of the pathogenic role of these cells and for development of therapeutic strategies aimed at fighting Th17-related diseases.

show abstract

“…It is likely that SCFA is one of the mediators, and ROR γ t + induction in Th17 and colonic Tregs may follow a different pathway [58]. Currently, availability of small-molecule inhibitors, such as TAK-828F, or activators of metabolic enzymes has made it possible to manipulate the metabolism of T cells and shift the Th17/Treg cell balance, providing a novel therapeutic option for the treatment of inflammatory and immune diseases [27, 63].…”

Section: Gut Microbiota and Cd4+ T Cell Differentiationmentioning

confidence: 99%

Gut Microbiota Modulation on Intestinal Mucosal Adaptive Immunity

Wang

Zhu

Qin

2019

Journal of Immunology Research

109

View full text Add to dashboard Cite

The mammalian intestine harbors a remarkable number of microbes and their components and metabolites, which are fundamental for the instigation and development of the host immune system. The intestinal innate and adaptive immunity coordinate and interact with the symbionts contributing to the intestinal homeostasis through establishment of a mutually beneficial relationship by tolerating to symbiotic microbiota and retaining the ability to exert proinflammatory response towards invasive pathogens. Imbalance between the intestinal immune system and commensal organisms disrupts the intestinal microbiological homeostasis, leading to microbiota dysbiosis, compromised integrity of the intestinal barrier, and proinflammatory immune responses towards symbionts. This, in turn, exacerbates the degree of the imbalance. Intestinal adaptive immunity plays a critical role in maintaining immune tolerance towards symbionts and the integrity of intestinal barrier, while the innate immune system regulates the adaptive immune responses to intestinal commensal bacteria. In this review, we will summarize recent findings on the effects and mechanisms of gut microbiota on intestinal adaptive immunity and the plasticity of several immune cells under diverse microenvironmental settings.

show abstract

Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available RORγt inverse agonist

Cited by 28 publications

References 45 publications

Role of Interleukin-17 in Acute Pancreatitis

Role of Interleukin-17 in Acute Pancreatitis

Transcriptional Regulators of T Helper 17 Cell Differentiation in Health and Autoimmune Diseases

Gut Microbiota Modulation on Intestinal Mucosal Adaptive Immunity

Contact Info

Product

Resources

About