Project description:Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its’ involvement in a variety of diseases, STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here, we identify AK59 as a STING degrader leveraging HERC4, a HECT-domain E3 ligase. Additionally, our data reveals that AK59 is effective on the common pathological STING mutations, suggesting a potential clinical application of this mechanism. Thus, these findings introduce HERC4 to the field of TPD and a compound-induced degradation of STING, suggesting potential therapeutic applications.

2024-04-12 | PXD046677 | Pride

Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease

Project description:The long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon is the only active autonomously replicating retrotransposon in the human genome. L1 harms the cell by inserting new copies, generating DNA damage, and triggering inflammation. Therefore, L1 inhibition could be used to treat many diseases associated with these processes. Previous research has focused on inhibition of the L1 reverse transcriptase due to the prevalence of well-characterized inhibitors of related viral enzymes. Here we present the L1 endonuclease as another target for reducing L1 activity. We have characterized structurally diverse small molecule endonuclease inhibitors using computational, biochemical, and biophysical methods. We also show that these inhibitors reduce L1 retrotransposition, L1-induced DNA damage, and inflammation reinforced by L1 in senescent cells. These inhibitors could be further used to better understand the life cycle of this element and its impact on human health.

2023-11-17 | GSE244265 | GEO

AMPK inhibitors may be potential drugs for STING-induced inflammatory diseases.

Project description:AMPK inhibitors suppress inflammatory gene expression induced by STING R284S variants.

2019-02-27 | GSE111197 | GEO

Identification of small molecule inhibitors of the Pathogen Box against Vibrio cholerae

Project description:Identification of small molecule inhibitors of the Pathogen Box against Vibrio cholerae

| PRJNA769742 | ENA

Cellular active small molecule inhibitors of Mycobacterium tuberculosis by NMR fragment screen

Project description:Cellular active small molecule inhibitors of Mycobacterium tuberculosis by NMR fragment screen.

2015-01-01 | GSE17424 | GEO

Study of Covalent Menin Inhibitor BMF-219 in Adult Patients With KRAS Driven Non-Small Cell Lung Cancer, Pancreatic Cancer, and Colorectal Cancer

Project description:A Phase 1/1b dose finding study to determine the OBD(s) and RP2D(s) of BMF-219, a covalent menin inhibitor small molecule, in subjects with KRAS mutated unresectable, locally advanced, or metastatic NSCLC (Cohort 1), PDAC (Cohort 2), and CRC (Cohort 3).

| 919 | ecrin-mdr-crc

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