Small molecule approaches to treat autoimmune and inflammatory diseases (Part III): Targeting cytokines and cytokine receptor complexes

Chen, Dongdong; Xu, Jie; Ding, Xiao; Wu, Yao; Shen, Hong C.; Tan, Xuefei

doi:10.1016/j.bmcl.2021.128229

Cited by 12 publications

(4 citation statements)

References 108 publications

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“…Targeting the protein–protein interaction interface remains a challenging task in drug discovery and development . Our previously discovered iST2-1 that blocked the binding between ST2 and IL-33 represents one of the few small-molecule inhibitors that target cytokine receptors . Based on our recently reported compound 4 , we obtained 32 (or XY52 ) exhibiting improved activities in biochemical, cell-based reporter assays and the in vitro MLR experiment that models the allo-reaction of T-cell activation.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic Mitigation of Acute Graft versus Host Disease by Novel 2-(Pyrrolidin-1-ylmethyl)pyrrole-Based Stimulation-2 (ST2) Inhibitors

Yuan

Jiang

et al. 2023

ACS Pharmacol. Transl. Sci.

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Hematopoietic cell transplantation (HCT) is a proven and potentially curable therapy for hematological malignancies and inherited hematological disease. The main risk of HCT is the development of graft versus host disease (GVHD) acquired in up to 50% of patients. Upregulation of soluble ST2 (sST2) is a key clinical biomarker for GVHD prognosis and was shown to be a potential therapeutic target for GVHD. Agents targeting sST2 to reduce the sST2 level after HCT have the potential to mitigate GVHD progression. Here, we report 32 (or XY52) as the lead ST2 inhibitor from our optimization campaign. XY52 had improved inhibitory activity and metabolic stability in vitro and in vivo. XY52 suppressed proinflammatory T-cell proliferation while increasing regulatory T cells in vitro. In a clinically relevant GVHD model, a 21-day prophylactic regimen of XY52 reduced plasma sST2 and IFN-γ levels and GVHD score and extended survival in mice. XY52 represented a significant improvement over our previous compound, iST2-1, and further optimization of XY52 is warranted. The small-molecule ST2 inhibitors can potentially be used as a biomarker-guided therapy for mitigating GVHD in future clinical applications.

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Section: Discussionmentioning

confidence: 99%

Prophylactic Mitigation of Acute Graft versus Host Disease by Novel 2-(Pyrrolidin-1-ylmethyl)pyrrole-Based Stimulation-2 (ST2) Inhibitors

Yuan

Jiang

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…The cytokine microenvironment, and the intracellular and extracellular metabolic signals play a pivotal role in controlling the balance between regulatory and antibody-producing B cell subsets [ 32 ]. Cytokines are a vital component in the host immune system, and cytokine-receptor cross-reactivity and related signaling pathways are considered to be the primary drivers of cytokine pleiotropy [ 36 ]. Furthermore, various DEG were observed to participate in nine cytokine related enriched biological processes, including interferon-gamma, interleukin-18 and interleukin-6 cytokine production and the chemokine biosynthetic process.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of spleen B cell revealed the molecular basis of bursopentin on B cell differentiation

Zhang

Cai

Hao

et al. 2022

Vet Res

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The bursa of Fabricius, the acknowledged humoral immune organ unique to birds, plays a vital role in B cell development. Bursopentin (BP5) derived from the bursa is reported to induce the development and formation of B cells. However, the mechanism of BP5 on B cell differentiation is still unclear. In this paper, total B lymphocytes from mice immunized with H9N2 subtype AIV vaccine were stimulated with BP5. The results show that BP5 at the experimental dosages promoted B cell differentiation, including the total B cells, activated B cells, differentiated B cells, mature B cells and plasma cells. Then, the in vivo immune experiment proved that the percentages of activated and differentiated B cells from mice immunized with AIV vaccine and 0.25 mg/mL BP5 were increased. To investigate the molecular mechanism of BP5 on B cell differentiation, the gene expression profiles of B cells purified from the spleen cells of mice immunized with AIV vaccine and BP5 were detected following RNA sequencing technology. The results show that BP5 at 0.05 and 0.25 mg/mL induced the enrichment of various biological functions, and stimulated five common significant enrichment pathways in B cells from the immunized mice. Additionally, 120 and 59 differentially expressed genes (DEG) represented transcriptional factors in B cells following 0.05 and 0.25 mg/mL BP5 immunization, respectively. In summary, these results suggest that BP5 regulates various gene expression involved in regulation of B cell development, which provides the knowledge required for additional studies on B cell differentiation in response to bursal-derived peptides and also provides an important experimental basis for improving vaccine immunity.

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“…An alternative approach is to design small molecules that target IL‐17A directly. Targeting cytokines and cytokine receptors with small molecules has become increasingly possible with advances in screening assays, computational analysis, and medicinal chemistry 17 …”

Section: Figurementioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL‐17A (LY3509754): A Phase I Randomized Placebo‐Controlled Study

Datta‐Mannan,

Regev,

Coutant

et al. 2024

Clin Pharma and Therapeutics

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For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)‐17A may represent a convenient alternative to IL‐17A‐targeting monoclonal antibodies. This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL‐17A target engagement profile of single or multiple oral doses of the small molecule IL‐17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10–2,000 mg) or multiple ascending dose (MAD; dose range 100–1,000 mg daily for 14 days) cohorts. The study enrolled 91 participants (SAD, N = 51 and MAD, N = 40) aged 21–65 years (71% men). LY3509754 had a time to maximum concentration (Tmax) of 1.5–3.5 hours, terminal half‐life of 11.4–19.1 hours, and exhibited dose‐dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL‐17A levels within 12 hours of dosing. Four participants from the 400‐mg (n = 1) and 1,000‐mg (n = 3) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset ≥ 12 days post‐last LY3509754 dose), consistent with drug‐induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte‐rich, moderate‐to‐severe lobular inflammation. We theorize that the DILI relates to an off‐target effect rather than IL‐17A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once‐daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated.

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Small molecule approaches to treat autoimmune and inflammatory diseases (Part III): Targeting cytokines and cytokine receptor complexes

Cited by 12 publications

References 108 publications

Prophylactic Mitigation of Acute Graft versus Host Disease by Novel 2-(Pyrrolidin-1-ylmethyl)pyrrole-Based Stimulation-2 (ST2) Inhibitors

Prophylactic Mitigation of Acute Graft versus Host Disease by Novel 2-(Pyrrolidin-1-ylmethyl)pyrrole-Based Stimulation-2 (ST2) Inhibitors

Transcriptomic analysis of spleen B cell revealed the molecular basis of bursopentin on B cell differentiation

Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL‐17A (LY3509754): A Phase I Randomized Placebo‐Controlled Study

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