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.

Acoramidis (AG10), an oral, second-generation stabilizer of the tetrameric transthyretin (TTR) protein, was submitted for FDA approval on Dec. 5, 2023 by BridgeBio for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). The rare but potentially fatal disease is characterized by amyloid deposits in heart muscle. The molecule has the potential to be best-in-class relative to Pfizer’s $2.4B+/yr blockbuster tafamidis. This story highlights early experiments validating TTR stabilization, why enthalpy of binding was key, how it binds TTR, its 30-mo clinical data, and more.

“compound 12” is a selective inhibitor of integrin αvβ5, a potential target for sepsis due to its potential role in regulating vascular leakage. Selectivity among integrin family members can be challenging to achieve and can have significant safety implications – hence, most integrin drugs have been selective biologics. Since the biological [...]

“compound 23” is an oral, selective Factor XIa inhibitor intended as an anticoagulation agent. Since the clinical translatability of FXIa inhibition in preclinical models hasn’t been established, this program was driven by activity in in vitro human plasma coagulation assays. The team was able to turn a 0.6 uM hit originally from a complement [...]

Nerandomilast (BI 1015550) is Boehringer Ingelheim’s PDE4B inhibitor with demonstrated clinical potential in treating IPF.