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.

Vertex’s VX-548 is a potential first-in-class, exquisitely selective, oral NaV1.8 inhibitor that recently captured headlines for its positive Ph. III data. With the ongoing opioid epidemic throughout the US, there is an urgent unmet medical need for non-addictive pain medications as alternatives to opioids. They plan to file an NDA by mid-2024 for the treatment of moderate-to-severe acute pain. This case study highlights what’s publicly known about Vertex’s journey in pain leading up to the Ph. III readout for VX-548, and why this is such a watershed moment for pain management.

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 [...]

Cerevance’s CVN293 is an oral, CNS-penetrant, selective inhibitor of potassium efflux-mediated NLRP3-inflammasome activation in microglia for the treatment of neurodegenerative disorders. Cerevance’s NETSseq platform was used to discover a microglia-specific potassium efflux channel, KCNK13, which allows modulation of the NLRP3-inflammasome in the CNS without affecting peripheral innate immunity. Read the full article to discover highlights on the CNS-penetration of highly polar compounds and how particle size can be key to oral bioavailability

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.