Delving into the Latest Updates on T-5224 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

c-Fos x c-Jun

Mechanism

c-Fos inhibitors(Fos proto-oncogene, AP-1 transcription factor subunit inhibitors), c-Jun inhibitors(Transcription factor Jun inhibitors)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Rheumatoid Arthritis

Originator Organization

FUJIFILM Holdings Corp.

Active Organization-

Inactive Organization

FUJIFILM Holdings Corp.Toyama Chemical Co., Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC29H27NO8

InChIKeyDALCQQSLNPLQFZ-UHFFFAOYSA-N

CAS Registry530141-72-1

In mammals, elongation of very long-chain fatty acids protein 6 (ELOVL6) play a role in both the elongation of fatty acids and the development of associated inflammation. However, the function and transcriptional regulatory mechanisms of Elovl6 in invertebrates are poorly understood. This study aimed to examine the function of Elovl6 and its transcriptional regulatory mechanism in Scylla paramamosain. RNA interference experiments showed that elovl6 knockdown significantly affected the synthesis and catabolism of hepatopancreatic lipids, leading to an increase in triglyceride levels and saturated fatty acid content, and a decrease in polyunsaturated fatty acid content. Notably, antioxidant capacity and immune function were also impaired, with decreased activity of antioxidant enzymes and immune-related genes. To investigate the transcription regulation of elovl6, a 2212-bp promoter fragment upstream of elovl6 was cloned and characterized. Analysis of the luciferase reporter showed that Ap-1 regulates elovl6 transcription via the -353 to -343 binding site. In vivo injection of the Ap-1 inhibitor T-5224 verified its inhibitory effect on elovl6 expression, with results similar to those of elovl6 knockdown, indicating that Ap-1 regulates lipid metabolism, antioxidant capacity, and immune function via Elovl6.

01 Oct 2024·Bioorganic Chemistry

Novel PROTAC probes targeting FOSL1 degradation to eliminate head and neck squamous cell carcinoma cancer stem cells

Article

Author: Huang, Boshi ; Ma, Zhikun ; Rilee, Grace ; Li, Jiong ; Zhang, Yan ; Zaman, Shadid U ; Pagare, Piyusha P

Previously, we identified that AP-1 transcription factor FOSL1 is required to maintain cancer stem cells (CSCs) in HNSCC, and an AP-1 inhibitor, T-5224, can eliminate HNSCC CSCs. However, its potency is relatively low, and furthermore, whether T-5224 eradicates CSCs through targeting FOSL1 and whether FOSL1 serves as an effective target for eliminating CSCs in HNSCC, require further validation. We first found that T-5224 can bind to FOSL1 directly. As a proof-of-principle, several cereblon (CRBN)-recruiting PROTACs were designed and synthesized using T-5224 as a warhead for more effective of targeting FOSL1. The top compound can potently degrade FOSL1 in HNSCC, thereby effectively eliminating CSCs to suppress HNSCC tumorigenesis, with around 30 to 100-fold improved potency over T-5224. In summary, our study further validates FOSL1 as an effective target for eliminating CSCs in HNSCC and suggests that PROTACs may provide a unique molecular tool for the development of novel molecules for targeting FOSL1.

01 Sep 2024·Diabetes

The Role of Activator Protein-1 Complex in Diabetes-Associated Atherosclerosis: Insights From Single-Cell RNA Sequencing

Article

Author: Jandeleit-Dahm, Karin A.M. ; Zhou, Ying ; Sharma, Arpeeta ; Khan, Abdul Waheed ; Calkin, Anna C. ; Murphy, Andrew J. ; Dai, Aozhi ; Watson, Anna M.D. ; Sourris, Karly C. ; Maxwell, Scott ; Aziz, Misbah ; Lee, Man K.S. ; Cooper, Mark E. ; Baratchi, Sara

Despite advances in treatment, atherosclerotic cardiovascular disease remains the leading cause of death in patients with diabetes. Even when risk factors are mitigated, the disease progresses, and thus, newer targets need to be identified that directly inhibit the underlying pathobiology of atherosclerosis in diabetes. A single-cell sequencing approach was used to distinguish the proatherogenic transcriptional profile in aortic cells in diabetes using a streptozotocin-induced diabetic Apoe−/− mouse model. Human carotid endarterectomy specimens from individuals with and without diabetes were also evaluated via immunohistochemical analysis. Further mechanistic studies were performed in human aortic endothelial cells (HAECs) and human THP-1–derived macrophages. We then performed a preclinical study using an activator protein-1 (AP-1) inhibitor in a diabetic Apoe−/− mouse model. Single-cell RNA sequencing analysis identified the AP-1 complex as a novel target in diabetes-associated atherosclerosis. AP-1 levels were elevated in carotid endarterectomy specimens from individuals with diabetes compared with those without diabetes. AP-1 was validated as a mechanosensitive transcription factor via immunofluorescence staining for regional heterogeneity of endothelial cells of the aortic region exposed to turbulent blood flow and by performing microfluidics experiments in HAECs. AP-1 inhibition with T-5224 blunted endothelial cell activation as assessed by a monocyte adhesion assay and expression of genes relevant to endothelial function. Furthermore, AP-1 inhibition attenuated foam cell formation. Critically, treatment with T-5224 attenuated atherosclerosis development in diabetic Apoe−/− mice. This study has identified the AP-1 complex as a novel target, the inhibition of which treats the underlying pathobiology of atherosclerosis in diabetes.Article Highlights

100 Deals associated with T-5224

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