Vorasidenib (AG-881) is a brain-penetrant allosteric inhibitor of mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) from Agios and Celgene that made headlines summer 2023 due to its stunning efficacy for treatment of glioma in patients with mIDH1/2. This Featured Case Study reviews how it was discovered, how it works, and why it matters.

AstraZeneca recently disclosed the structure and discovery journey of their oral small molecule PCSK9 inhibitor, AZD0780, during the ACS Fall 2024 First Time Disclosures session in Denver. Discover how the team identified a fragment hit targeting a previously unexplored pocket, verified its novel mechanism of action, and successfully advanced it into a clinical compound now in Ph. II trials for patients with dyslipidemia.

Kymera’s KT-413 is a CRBN-based dual-mechanism degrader that degrades both IRAK4 and the transcription factors IKZF1/3, acting as an IMiD, with promising clinical activity for the treatment of ABC-like subtype of DLBCL. This fascinating case study demonstrates how a dual-mechanism degrader of IKZF1/3 and IRAK4 can be designed to maximize NF-κB inhibition while simultaneously upregulating the Type I interferon response. This approach restores the apoptotic response and enables oncogene-mediated cell death, resulting in a robust antiproliferative and pro-apoptotic effect in MYD88 mutants.

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.

Atrasentan, an ETA receptor antagonist discovered by Abbott (AbbVie) in the 1990s, was initially developed for prostate cancer. Due to insufficient clinical data for approval, AbbVie shifted its focus to chronic kidney diseases, conducting a large trial (SONAR) with over 5,000 patients. AbbVie later exited kidney disease drug development and out-licensed atrasentan to Chinook. Novartis then surprised everyone with a $3.2B buyout of Chinook. This case exemplifies the complexities of drug discovery for kidney diseases and the long journey from initial research to clinical success.