Delving into the Latest Updates on BX-912 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

BX 912, BX-912, BX912

Target

PDPK1 x SOX17

Action

inhibitors, agonists

Mechanism

PDK1 inhibitors(3-phosphoinositide-dependent protein kinase 1 inhibitors), SOX17 agonists(SRY-box transcription factor 17 agonists)

Therapeutic Areas

NeoplasmsRespiratory DiseasesOther Diseases

Active Indication

Pulmonary Arterial HypertensionNeoplasms

Inactive Indication-

Originator Organization

Berlex Biosciences

Active Organization

Imperial College LondonBerlex Biosciences

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC20H23BrN8O

InChIKeyDMMILYKXNCVKOJ-UHFFFAOYSA-N

CAS Registry702674-56-4

Radiotherapy is a common approach during the treatment of thyroid cancer (THCA). It is urgent to identify the radiotherapy-related gene and explore the underlying mechanisms. An message RNA expression clinical data was gained from the Cancer Genome Atlas. The differential expression genes between normal individuals and THCA patients were identified by the “limma” package of R software. The differential expression genes between the patients without radiation therapy and the patients with radiation therapy were also obtained via the same method. Survival analysis, gene set enrichment analysis, immune analysis, drug sensitivity analysis, gene–miRNA, and nomogram analysis were performed to explore the radiotherapy-related gene value. The results showed that 354 DGEs between the THCA patients without radiation therapy and THCA patients with radiation therapy including the 148 up-regulated genes and 206 down-regulated were screened and displayed by volcano plot. A gene enrichment analysis showed radiation-related genes were enriched in various pathways such as mineral absorption, complement and coagulation cascades, B cell receptor signaling pathway, salivary secretion, and hematopoietic cell lineage. Then the hub-related-radiotherapy prognosis gene LRP1B was identified. The expression analysis showed that the LRP1B expression level was higher in normal individuals than in THCA patients with an obvious difference via T test in independent samples and paired samples. Immune analysis results showed that the stroma score, immune score, and ESTIMATES score were higher in the low-risk score than in the high-risk score. LRP1B is a vital gene that executes function via a variety of pathways in THCA patients with radiotherapy. Radiotherapy could reduce the expression of LRP1B and AL356596.1. Moreover, the constructed nomogram is based on risk score and clinical features, and it had a great function in predicting survival time for patients.

01 Dec 2024·Journal of Advanced Research

FTO activates PD-L1 promotes immunosuppression in breast cancer via the m6A/YTHDF3/PDK1 axis under hypoxic conditions

Article

Author: Cao, Shihan ; Gao, Song ; Wang, Siyu ; Pang, Da ; Zhang, Xingda ; Li, Guozheng ; Gong, Yajie ; Wu, Hao ; Chen, Quanrun ; Zhao, Shilu ; Wang, Jianyu ; Wang, Xinheng

INTRODUCTION:

Altered epigenetic reprogramming enables breast cancer cells to adapt to hypoxic stress. Hypoxic microenvironment can alter immune cell infiltration and function, limiting the effectiveness of immunotherapy.

OBJECTIVES:

The study aimed to identify how fat mass and obesity-associated protein (FTO) helps breast cancer cells cope with the hypoxic microenvironment and the mechanisms behind breast cancer cell resistance to tumor immunity.

METHODS:

Clinical samples were utilized to analyze the impact of FTO on breast cancer progression and the effect of programmed cell death protein 1/ programmed cell death 1 ligand 1(PD-1/PD-L1) immune checkpoint inhibitor treatment. Utilized MeRIP-seq and mRNA-seq to analyze the downstream genes regulated by FTO under hypoxia. Methylation modification regulation of PDK1 by FTO was clarified using RIP. Then mouse models were utilized to analyze the efficacy of inhibiting FTO and 3-Phosphoinositide-dependent protein kinase 1(PDK1) in combination with PD-1/PD-L1 immune checkpoint inhibitor treatment.

RESULT:

N6-Methyladenosine(m⁶A) demethylase FTO was transcriptionally activated by hypoxia inducible factor 1α(HIF-1α). PDK1 was identified as a potential target of FTO under hypoxic conditions through high-throughput sequencing. Mechanistically, overexpression of FTO decreases m⁶A modification sites on PDK1 mRNA, preventing YTH domain family 3(YTHDF3) from recognizing and binding to these sites, thereby inhibiting the degradation of PDK1 mRNA. Overexpression of PDK1 activates the AKT/STAT3 pathway, leading to enhanced PD-L1 expression. Targeting the FTO and PDK1-AKT pathways with FB23 and BX-912 inhibit breast cancer growth, enhance cytotoxic T lymphocyte (CTL) activity, and enhance the effectiveness of the PD-1/PD-L1 checkpoint inhibitor Atezolizumab.

CONCLUSION:

This study reveals that HIF-1α promotes FTO transcription under hypoxic conditions, thereby increasing PD-L1 expression through the PDK1/AKT/STAT3 axis. Inhibition of FTO and PDK1 under hypoxic conditions could serve as a promising immunotherapeutic strategy for breast cancer.

20 Jul 2024·BIOMEDICAL AND ENVIRONMENTAL SCIENCES

Multi-omics Approach Reveals Influenza-A Virus Target Genes Associated Genomic, Clinical and Immunological Characteristics in Cancers.

Article

Author: Chen, Chun Bo ; Wang, Jiao Jiao ; Ye, Wei le ; Liao, Wei Xiong ; Liu, Zhi Ping ; Huang, Zun Nan ; Liao, Yong ; Liu, Yong ; Xiao, Chun Xia ; Yang, Ping Lian

Objective:

To examine the precise function of influenza A virus target genes (IATGs) in malignancy.

Methods:

Using multi-omics data from the TCGA and TCPA datasets, 33 tumor types were evaluated for IATGs. IATG expression in cancer cells was analyzed using transcriptome analysis. Copy number variation (CNV) was assessed using GISTICS 2.0. Spearman's analysis was used to correlate mRNA expression with methylation levels. GSEA was used for the enrichment analysis. Pearson's correlation analysis was used to examine the association between IATG mRNA expression and IC50. The ImmuCellAI algorithm was used to calculate the infiltration scores of 24 immune cell types.

Results:

In 13 solid tumors, IATG mRNA levels were atypically expressed. Except for UCS, UVM, KICH, PCPG, THCA, CHOL, LAMI, and MESO, most cancers contained somatic IATG mutations. The main types of CNVs in IATGs are heterozygous amplifications and deletions. In most tumors, IATG mRNA expression is adversely associated with methylation. RT-PCR demonstrated that EGFR, ANXA5, CACNA1C, CD209, UVRAG were upregulated and CLEC4M was downregulated in KIRC cell lines, consistent with the TCGA and GTEx data.

Conclusion:

Genomic changes and clinical characteristics of IATGs were identified, which may offer fresh perspectives linking the influenza A virus to cancer.

100 Deals associated with BX-912

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	Preclinical	United Kingdom	Imperial College London	16 May 2025
Neoplasms	Preclinical	United States	Berlex Biosciences	01 May 2005