Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1.

Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as a negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation of immune function and has demonstrated synergy with immune checkpoint inhibitors in syngeneic mouse cancer models. These data offer compelling evidence for the use of selective small molecule inhibitors of HPK1 in cancer immunotherapy.

Regulating the work function of silver catalysts surface engineering for enhanced CO electroreduction.

The work function can serve as a characteristic quantity to evaluate the catalytic activity due to its relationship with the surface structure of a material. However, what factors determine the influence of the work function on the electrochemical performance are still unclear. Herein, we elucidate the effect of the work function of Ag on the electrochemical reduction of CO to CO by controlling the ratio of exposed crystalline planes.

Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).

Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced T-cell activation. Studies using HPK1 kinase-dead knock-in animals have demonstrated the loss of HPK1 kinase activity resulted in an increase in T-cell function and tumor growth inhibition in glioma models. Herein, we describe the discovery of a series of small molecule inhibitors of HPK1.

Cross-Sectional Study on Health Literacy and Internet Accessibility Among Patients With DM in Gansu, China.

To determine the relationship between the health literacy of patients with diabetes mellitus (DM) and the accessibility of internet surfing for information concerning DM. A multistage stratified sampling method was utilized to conduct a questionnaire survey on DM health literacy and internet accessibility among 1,563 patients with DM in Gansu Province in 2020. Logistic regression was performed to analyze the factors that influence health literacy and internet accessibility; while the chi-square test was used to compare the differences in needs.

GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved Profile.

The -methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca and Na. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs.

Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.

The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer's disease. Herein we describe the discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from a high-throughput screening hit.