Combined Peptide and Small-Molecule Approach Toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction
The NRF2/ARE signalling pathway is a key mediator in oxidative stress and therefore a potential target for neuroprotective agents. The publication describes the identification of nonacidic tetrahydroisoquinolines (THIQs) that inhibit the interaction between NRF2 and its main negative regulator KEAP1. The approach utilized structural information from peptide screening at the P2 pocket, noncovalent small-molecule inhibitors, and the outcome from an explorative SAR at position 5 of THIQs to identify a series of neutral THIQ analogs that bind to KEAP1 in the low micromolar range. X-ray crystallography studies reveal the novel binding mode of these molecules to KEAP1.
Dihydroxypyrimidine Scaffold to Target HIV‑1 Nucleocapsid Protein
IRBM and their collaborators’ at the universities of Strasbourg and Siena have recently published a paper in the ACS Medicinal Chemistry Letters which describes their approach to the identification of a 5-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. The HIV-1 nucleocapsid (NC) protein is a target of great interest because it is essential for viral replication. A bioisosteric catechol replacement approach led to identification the 5-dihydroxypyrimidine-6-carboxamide scaffold and subsequent hit validation efforts generated optimized analogs showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.
IRBM publishes in Nature Scientific Reports on the Janus effect of glucocorticoids on the differentiation of muscle fibro/adipogenic progenitors
Fibro-adipogenic progenitors (FAPs) are known to cause muscle impairment in non-physiological settings, such as aging and myopathies, by promoting fibrosis and fat infiltration. IRBM and their collaborators at the University of Rome Tor Vergata, screened a library of 1,120 FDA/EMEA approved drugs using high content screening (HCS) to identify potential inhibitors of adipogenic differentiation of FAPs. The resulting hits contained a remarkable number of glucocorticoids (GCs) – drugs known to promote adipogenesis. Three of the GCs identified by the screen were further investigated by different approaches. The findings showed that GCs have additional effects to their known anti-inflammatory properties, affecting muscle homeostasis and physiology.