Yan Chen

NaV1.8, a member of the voltage-gated sodium channel (NaV) family, is predominantly expressed in peripheral sensory neurons. Based on rodent NaV1.8 knockout and knockdown studies and a 2012 report of gain-of-function mutations in humans, NaV1.8 has been linked to nociceptive, inflammatory, and neuropathic pain, including chronic neuropathic pain. This compound roundup provides a historical recap of both preclinical and clinical NaV1.8 inhibitors that shaped the landscape for the new era of pain management we are witnessing today.

NaV1.8 has become an industry focal point in the pursuit of pain therapeutics thanks to the success of Vertex’s selective inhibitor, VX-548, in Ph. III clinical trials for acute pain and Ph. II results in diabetic peripheral neuropathy. Unlike opioid receptor modulation, NaV1.8 inhibition does not carry the same addiction risks in part due to its lack of expression in the brain. Following our recent review of the leading NaV1.8 inhibitor VX-548, this article provides more details on the history of target validation for NaV1.8 in pain and why this could be the new frontier for pain management.

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.

STC15 is Storm Therapeutics' first-in-class and first-to-clinic inhibitor of the post-transcriptional RNA modifier, METTL3, which progressed from HTS hit to clinical development in less than three years. METTL3 inhibitors have been previously identified, but no METTL3 inhibitors have entered clinical development until now. In this article, we explore METTL3 as a therapeutic target, highlight the discovery story of STC15, its fascinating mechanism of action, provide the latest clinical development update, and much more.

RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor from Relay Therapeutics. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to hyperglycemia and rash. RLY-2608 is currently in a Ph. I as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article reviews the discovery of RLY-2608, its mechanism of mutant selectivity, how it compares to other molecules, recent clinical developments, and more.

Kymera's KT-474 is the first oral degrader to demonstrate activity in clinical trials outside cancer and Sanofi recently started a Ph. II trial with the molecule in AD, restoring life to IRAK4 as an immunology target. This article highlights why Kymera’s KT-474 program is scientifically notable, including how it differentiates from small molecule inhibitors, potential competitiveness with biologics, the first reported cryo-EM ternary complex of a heterobifunctional degrader, and why this 2023 Molecule of the Year Nominee will likely be considered a “landmark in drug discovery” for some time.

BridgeBio’s acoramidis (Attruby), an oral, second-generation stabilizer of the TTR protein, has been approved by the FDA for the treatment of ATTR-CM (transthyretin amyloid cardiomyopathy). Amyloid deposits in the heart muscle characterize the rare but potentially fatal disease. This case study reviews the history of TTR modulation, early experiments validating the therapeutic potential of TTR stabilization, the binding mechanism of acoramidis to TTR, the importance of binding enthalpy for differentiation, and the molecule’s impressive 30-month clinical data following an early scare.