Identification of a Potent and Selective Focal Adhesion Kinase Proteolysis Targeting Chimera: Targeting Noncatalytic Functions of Focal Adhesion Kinase to Facilitate Antitumor Immunity.

Focal adhesion kinase (FAK) has emerged as a promising therapeutic target since its pivotal involvement in tumorigenesis. However, FAK inhibitors exhibit limited efficacy in suppressing FAK's noncatalytic functions, potentially compromising their therapeutic outcomes. Herein, we developed a series of FAK PROTACs derived from our previously characterized FAK inhibitor .

Discovery of a Potent FLT3 Inhibitor ()-4-(3-(3-Fluoro-4-(morpholinomethyl)styryl)-1-indazol-6-yl)pyridin-2-amine for the Treatment of Acute Myeloid Leukemia with Multiple FLT3 Mutations.

Targeting FLT3 genetic alterations has emerged as a promising therapeutic approach for AML. However, the rapid emergence of resistance to FLT3 inhibitors has severely curtailed their clinical utility. Herein, we developed a series of ()-4-(3-arylvinyl-1-indazol-6-yl)pyridin-2-amine derivatives to overcome FLT3 resistance mutations.

Design, synthesis and biological evaluation of 3-amino-6-(2-hydroxyphenyl)pyridazin-4-aryl derivatives as SMARCA2/4 degraders.

SMARCA2/4, a pair of mutually exclusive core catalytic subunits of the chromatin remodeling complex SWI/SNF, play essential roles in regulating gene transcription. Given the pivotal role of SMARCA2/4 in sustaining the oncogenic transcription program and promoting proliferation in acute myeloid leukemia (AML), the development of non-selective degraders holds practical therapeutic implications. Herein, we designed and synthesized a series of proteolysis-targeting chimeras (PROTACs) by conjugating the VHL ligand to a SMARCA2/4 bromodomain ligand, 2-(6-amino-5-phenylpyridazin-3-yl)phenol, using various linkers.

Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases.

Several mitochondrial dysfunctions in obesity and diabetes include impaired mitochondrial membrane potential, excessive mitochondrial reactive oxygen species generation, reduced mitochondrial DNA, increased mitochondrial Ca2+ flux, and mitochondrial dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria in physiological and pathological conditions. As a paradox, inhibition and activation of mitophagy have been observed in obesity and diabetes-related heart disorders, with both exerting bidirectional effects.

Integrated Microbiome and Serum Metabolome Analysis Reveals Molecular Regulatory Mechanisms of the Average Daily Weight Gain of Yorkshire Pigs.

The average daily weight gain (ADG) is considered a crucial indicator for assessing growth rates in the swine industry. Therefore, investigating the gastrointestinal microbiota and serum metabolites influencing the ADG in pigs is pivotal for swine breed selection. This study involved the inclusion of 350 purebred Yorkshire pigs (age: 90 ± 2 days; body weight: 41.

Cardiac-to-adipose axis in metabolic homeostasis and diseases: special instructions from the heart.

Adipose tissue is essential for maintaining systemic metabolic homeostasis through traditional metabolic regulation, endocrine crosstalk, and extracellular vesicle production. Adipose dysfunction is a risk factor for cardiovascular diseases. The heart is a traditional pump organ.