Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of . Compound is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (), indicating that may have lower EGFR wild-type associated toxicity.

Thymosin beta 4 prevents systemic lipopolysaccharide-induced plaque load in middle-age APP/PS1 mice.

Lipopolysaccharide (LPS) produced by the gut during systemic infections and inflammation is thought to contribute to Alzheimer's disease (AD) progression. Since thymosin beta 4 (Tβ4) effectively reduces LPS-induced inflammation in sepsis, we tested its potential to alleviate the impact of LPS in the brain of the APPswePS1dE9 mouse model of AD (APP/PS1) and wildtype (WT) mice. 12.

Eukaryotic translation initiation factor 4AII contributes to microRNA-122 regulation of hepatitis C virus replication.

Hepatitis C virus (HCV) is a positive sense RNA virus that persistently infects human liver, leading to cirrhosis and hepatocellular carcinoma. HCV replication requires the liver-specific microRNA-122 (miR-122). In contrast to canonical miRNA-mediated repression via 3'UTR sites, miR-122 positively regulates HCV replication by a direct interaction with the 5' untranslated region (UTR) of the viral RNA.

Pramipexole induced place preference after L-dopa therapy and nigral dopaminergic loss: linking behavior to transcriptional modifications.

Rationale: Impulsive-compulsive disorders (ICD) in patients with Parkinson's disease (PD) have been described as behavioral or substance addictions including hypersexuality, gambling, or compulsive medication use of the dopamine replacement therapy (DRT).

Objectives: A remaining challenge is to understand the neuroadaptations leading to reward bias in PD patients under DRT.

Methods: To this end, the appetitive effect of the D2/D3 agonist pramipexole was assessed after chronic exposure to L-dopa in an alpha-synuclein PD rat model.