LTGO-33 is a state-independent NaV1.8 inhibitor with over 600-fold selectivity for the NaV1.8 channel over other sodium channels. Chronic pain affects millions, and existing treatments offer limited efficacy, risk of abuse, and low tolerability. There is an urgent need for new drugs that target validated pain mechanisms such as NaV1.8, which has recently gained increased attention. This article explores the unique pharmacological properties of LTGO-33, setting it apart from earlier NaV1.8 inhibitors.

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

RMC-6236 is a non-covalent pan-RAS(ON) inhibitor from Revolution Medicines, which shows remarkable efficacy in tumors driven by RAS mutants that were previously considered “undruggable,” such as G12V/D/A/S, G13X, and Q61X. RMC-6236 exerts its action via a “tri-complex” mechanism, gluing RAS to the ubiquitously expressed chaperone protein, cyclophilin A. Our in-depth article covers the presentation given at the AACR 2024 meeting, which outlines the discovery and preclinical profile of RMC-6236 as well as the latest clinical updates.

JNJ-54175446 is an oral, CNS-penetrant P2X7 ion channel antagonist targeting a novel pathway linking neuroinflammation and depression, with recently published Ph. I data in major depressive disorder (NCT02902601, initiated in 2016). The Janssen program is notable as a pioneering early example of a neuroinflammation program started at a time before NLRP3 or neuroimmunology were commonly discussed topics, as they are today [...]

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.