Exploring the synergistic effects of cabozantinib and a programmed cell death protein 1 inhibitor in metastatic renal cell carcinoma with machine learning.

Clinical evidence supports the combination of cabozantinib with an immune checkpoint inhibitor for the treatment of metastatic clear cell renal cell carcinoma (mccRCC) and suggests a synergistic antitumour activity of this combination. Nevertheless, the biological basis of this synergy is not fully characterized. We studied the mechanisms underpinning the potential synergism of cabozantinib combined with a PD1 inhibitor in mccRCC and delved into cabozantinib monotherapy properties supporting its role to partner these combinations.

Chemoproteomic Approach to Explore the Target Profile of GPCR ligands: Application to 5-HT1A and 5-HT6 Receptors.

Determination of the targets of a compound remains an essential aspect in drug discovery. A complete understanding of all binding interactions is critical to recognize in advance both therapeutic effects and undesired consequences. However, the complete polypharmacology of many drugs currently in clinical development is still unknown, especially in the case of G protein-coupled receptor (GPCR) ligands.

Chemical probes for the recognition of cannabinoid receptors in native systems.

Receptors made visible: The described biotin-tagged small-molecule probes with excellent affinities for the CB(1) and CB(2) cannabinoid receptors (CB(1)R and CB(2)R) enable direct visualization of these receptors in native cellular systems, including neurons, microglia, and immune cells. This method could overcome some of the limitations of current methodologies and may help to dissect the complexity of the endogenous cannabinoid system.

Development of endocannabinoid-based chemical probes for the study of cannabinoid receptors.

We report the synthesis of new chemical probes (1a,b, 2a-c, 3a-c) based on the structure of the main endocannabinoids for their use in biological systems directly or via click chemistry. As proof of concept, 2-arachidonyl glyceryl ether based biotinylated 3b enables direct visualization of CB(1) receptor in cells. These results represent the starting point for the development of advanced small molecule chemical probes able to generate valuable information about the cannabinoid receptors.

Ligand-based approach to in silico pharmacology: nuclear receptor profiling.

Bioactive ligands are a valuable and increasingly accessible source of information about protein targets. On the basis of this statement, a list of 25 nuclear receptors was described by a series of bioactive ligands extracted directly from bibliographical sources, stored properly in an annotated chemical library, and mathematically represented using the recently reported SHED molecular descriptors. Analysis of this ligand information allowed for derivation of a threshold of nuclear receptor concern.