VVD-214/RO7589831 is an oral covalent, reversible, and allosteric inhibitor of WRN helicase discovered by the San Diego-based biotech Vividion Therapeutics and being developed by Roche for tumors marked by microsatellite instability and/or mismatch repair deficiency. Vividion has utilized its chemoproteomics platform to discover and develop novel treatment options for oncology targets. The structure and initial preclinical pharmacology data for VVD-214 were recently disclosed at the AACR Annual Meeting 2024 in San Diego. VVD-214 is currently being evaluated in a Ph. I trial.

Sonrotoclax, BeiGene’s clinical-stage, orally bioavailable, next-generation inhibitor, targets both WT and mutated forms of the Bcl-2 protein by binding within a hydrophobic groove, similar to other inhibitors in its class. Explore this case study to see how sonrotoclax was rationally designed to potency against both WT and mutant Bcl-2 and address the limitations of first-generation inhibitors and more!

Arvinas’ ARV-393 is an orally bioavailable PROTAC that degrades BCL6 via CRBN-mediated ubiquitination and proteasomal degradation intended for the treatment of NHL. At the AACR San Diego 2024 meeting, Arvinas disclosed the structure and discovery story of this molecule, which exhibits first-in-class potential. This article covers the key SAR observations that led to the invention of this orally bioavailable PROTAC®, its performance in a triple-hit, high-grade BCL and R-CHOP-resistant cell line, and why sustaining BCL6 knockdown beyond 24 hours was critical for the success of this program.

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.

BAY 2925976 is a novel oral ARα2C antagonist developed by Bayer for the treatment of OSA (obstructive sleep apnea), a widespread condition affecting nearly one billion people globally. Despite the availability of mechanical treatments like CPAP, poor adherence rates highlight the need for more effective interventions. BAY 2925976 demonstrated a preclinical proof of concept for ARα₂C modulation as a potential therapeutic approach for OSA. In this article, we detail the discovery of BAY 2925976, as highlighted by Michael Hahn at the ACS Fall 2024 First-Time Disclosures session in Denver, CO.