Infection with the malaria parasite, Plasmodium falciparum, is a leading cause of fatality in the tropical regions of the world, with over 240M infections and >600k deaths each year. Currently, over half of the world population is at risk of infection and with the rise of resistance against current treatments, the need for new antimalarials is clear. At the ACS Fall 2024 conference in Denver, CO, Novartis outlined the structure and discovery story of NVP-IWY357, a novel antimalarial that has no cross-resistance to current drugs and the potential to achieve a single-dose cure.

Jecure’s JT001 is a selective inhibitor of NLRP3 inflammasome and among the earlier compounds in this now highly competitive space. In 2018, Genentech bought Jecure Therapeutics for an undisclosed amount, gaining access to Jecure’s NLRP3 inhibitor JT001. While there are many other NLRP3 inhibitors now in the space, JT001 is an interesting example of an initial attempt to overcome liver toxicity with well-known NLRP3 inhibitor MCC950. However, the molecule ran into its own kidney toxicity issues, making this an intriguing toxicology case study.

Nuvalent’s lead compound, NVL-520, is an oral, brain-penetrant, TRK-sparing, and potential best-in-class ROS1 kinase inhibitor that recently entered Ph. II of the ARROS-1 trial (NCT05118789) in patients with advanced ROS1-positive NSCLC. This article highlights what makes the Nuvalent’s NVL-520 program scientifically notable, including what gives it a potential best-in-class profile as a ROS1 inhibitor, the emerging toxicology of hard-to-avoid off-targets, an interesting synthetic route to the small macrocycle, 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.

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.