Pfizer disclosed the structure and discovery of their oral small molecule BDK inhibitor/degrader, PF-07328948, during the ACS Fall 2024 First-Time Disclosures session in Denver. The team identified a thiophene carboxylic acid-based hit targeting an allosteric pocket on BDK. Through optimization, they overcame challenges such as potential IADRs and BDK-E2 complex stabilization. By manipulating the dihedral angle of the methoxy group, they enhanced binding interactions, verifying PF-07328948's unexpected mechanism of action in vivo. PF-07328948 is currently Ph. I trials.

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.

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.

In August 2024, seladelpar (LivdelziTM) became the first FDA-approved selective agonist of PPARδ (peroxisome proliferator-activated receptor δ), following an almost 20-year journey from the original discovery and patent publications. Originally developed by CymaBay in collaboration with Johnson & Johnson, approval was granted to Gilead Sciences following their February 2024 purchase of CymaBay Therapeutics for $4.3B. Seladelpar was approved as a second-line treatment for patients with primary biliary cholangitis.

JNT-517 is Jnana Therapeutics' first-in-class cryptic allosteric SLC6A19 inhibitor to treat phenylketonuria (PKU). This is a notable case study employing a novel lead generation approach with photoaffinity probes, leading to a clinical candidate for a historically challenging-to-drug target class. Read the case study to learn how Jnana used their RAPID technology to quickly generate allosteric inhibitor hits, the SAR that led to the discovery of JNT-517, and why the molecule is notable.