Recent Highlights in Covalent Drug Discovery

In the aftermath of the thalidomide tragedy, the FDA advised excluding females in the childbearing age from early-stage clinical trials. However, this policy resulted in the prolonged underrepresentation of women in clinical research, limiting knowledge about how drugs affect genders differently. Recent policy changes, including the NIH's emphasis on considering sex as a biological variable, aim to reduce these disparities by promoting more diverse clinical trial participation. This article explores the current landscape of endometriosis therapies and how it relates to women’s healthcare.

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.

The "New Drugs on the Horizon" sessions at the AACR Annual Meeting 2024 in San Diego revealed twelve innovative oncology agents and offered attendees a first look at their structures and preliminary data as they enter/progress in the clinic. In case you missed any of these exciting compounds – including selective CDK inhibitors, molecular glues, bifunctional degraders, a radiopharmaceutical, a bifunctional antibody, and an ADC – this article covers the structures and targets disclosed. A separate session disclosed the structure of a pan-RAS isoform inhibitor with remarkable clinical results.

There has been substantial interest in the development of screening methods capable of surveying a wider sample of chemical space and larger numbers of compounds. Over the past two decades, DEL technology has evolved into a broadly utilized and validated platform in drug discovery, yielding diverse hits for a wide range of biologically relevant targets. Read the full review for a historical and technical overview of DEL technology, including how libraries are prepared and screened, a comparison to other HTS methods, and examples of successful applications in drug discovery.

DILI is a leading cause of acute liver failure, accounting for half of these cases and often resulting in drug withdrawals. Understanding and managing DILI risk as a medicinal chemist involves exploring the intricate interplay among properties and structural features. In this article, we provide a medicinal chemist's perspective on the current understanding of DILI mechanisms, highlight cutting-edge assay developments for a holistic assessment, and discuss strategies for predicting DILI risks.