The Post-Gleevec Era

PRMT5 is an epigenetic “synthetic lethality” target that has attracted much attention among drug hunters. The first generation of PRMT5 inhibitors was limited by systemic toxicities resulting in a cooling of industry interest, until the recent identification of tumor-specific inhibitors. These second-generation compounds target the MTA:PRMT5 complex in MTAP-deleted cancers—15% of all tumors—leading to a revival of the target. Read on to find out which companies are prevailing in the search for a first-in-class PRMT5 inhibitor and how their clinical compounds differentiate.

One of the key challenges in CNS projects is achieving sufficient unbound brain exposure to engage the target. To predict CNS exposure, scientists employ metrics like CNS MPO scores from Pfizer and Merck, Bayesian models, and methods for balancing physicochemical properties. However, these in silico metrics often fail to correlate well with experimental data. Schrödinger's team has discovered the energy of solvation (E-sol) metric, which accurately predicts Kp,uu and has been validated with CNS-penetrant DLK inhibitors. Explore more in this detailed Drug Hunter article.

Among the small molecule highlights in January’s news were a $100M+ Series A for a PARP1 + PI3Kα-focused company, clinical data with an SLC inhibitor for PKU, a 5-HT2C superagonist for seizures, and a NK1,3 dual antagonist for women’s health. A novel anti-obesity agent from phenotypic screening also made headlines, and the close of a major acquisition may bring relief to the industry. You can read about these notable scientific highlights and more below.

The team reviews hundreds of compounds from thousands of papers, press releases, and other sources each month to select candidates for Molecules of the Month. Here we have compiled a table of >60 additional molecules that were of interest in December 2023 along with highlights from some of the team’s favorites in the article.

Genentech’s GDC-6599 is the first oral TRP Ankyrin 1 (TRPA1) antagonist to reach Ph. IIa (NCT05660850) for chronic cough after preclinical studies and a Ph. I trial showed it was well-tolerated, in contrast to prior molecules. The transient receptor potential (TRP) family of ion channels has been the subject of intensive drug discovery efforts due to their critical role in the development and progression of pain, itch, and respiratory conditions.