AZD4747 is a CNS-penetrant, oral KRAS G12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibitors have tended to be quite large and fall outside the range of physicochemical properties generally required for CNS permeability. (MW < 360 Da, cLogD < 2, TPSA < 90 Å2. AZD4747 is much smaller than marketed KRAS G12C inhibitors but maintains exceptional cellular potency. The team also encountered an unexpected toxicity that scientists working on covalents should pay attention to.

The Altos Therapeutics /Takeda D2/D3 receptor antagonist, TAK-906 , is a peripherally-restricted, non-BBB penetrant molecule, targeting the stomach and vomiting center in the area postrema to treat gastroparesis. Gastroparesis is a chronic condition characterized by delayed gastric emptying, resulting in nausea, vomiting, pain, and anorexia [...]

The Takeda AMPA-R potentiator, TAK-653 , is a glutamate-dependent potentiator that exhibits minimal agonism. AMPA-R agonism is associated with seizure risk and bell-shaped dose-response effects. As reviewer Jake Schwarz notes, companies including Cortex Pharmaceuticals (now RespireRx) and Lilly have been trying to develop AMPA modulators for [...]

NT-0796 is NodThera's pro-drug inhibitor of the NLRP3 inflammasome. NT-0796 is currently in a Ph. Ib/IIa trial in obese individuals at risk of developing atherosclerotic cardiovascular diseases. NT-0796 has the potential to reduce neuroinflammation in Parkinson’s disease. The NLRP3 inflammasome has emerged as a hot target due to its connection to Alzheimer’s disease, Parkinson’s disease, gout, and other diseases. Here is a detailed review of the role of NLRP3 inhibition in treating atherosclerosis, how NT-0796 was identified, and what makes it special, clinical development, and more.

KLS-13019 is a CBD (cannabidiol) analogue and GPR55 (G protein-coupled receptor 55) antagonist from Kannalife Sciences, which shows promise as a novel therapeutic for neuropathic pain, particularly chemotherapy-induced neuropathic pain.