Olutasidenib, discovered by Forma Therapeutics and marketed by Rigel, is an oral, brain-penetrant, selective mIDH1 inhibitor. It was granted Orphan Drug Designation and approved in December 2022 by the FDA for adults with relapsed/refractory acute myeloid leukemia. Approval was granted based on a Ph. I/II trial showing a 35% CR+CRh rate and a favorable 25.9-month median duration. This article describes the discovery and development of olutasidenib, how it is distinct from other mIDH inhibitors, and its potential in treating gliomas.

This article compiles recent high-profile clinical readouts and related news with small molecules of general interest and structures where they are available. Targets and indications discussed in this article include BTK for MS, Axl, TYRO3, and Mer for oncology, HIF prolyl-hydroxylase in anemia, ET/AT in nephrology, a JAK2 inhibitor for myelofibrosis, and THR-beta in NASH. [...]

Small molecule drugs make up most of the drugs we take conveniently as pills, including painkillers like ibuprofen (Advil), antibiotics like penicillin and amoxicillin, or cholesterol-lowering drugs like atorvastatin (Lipitor). The biotechnology revolution allowed scientists to create drugs through genetic engineering and related biological processes, creating a new category of drugs known as “biologics.”...

“Compound 25” is a selective, CNS-penetrant, ATP-competitive LRRK2 inhibitor that entered preclinical candidate enabling studies but was discontinued for undisclosed reasons. The molecule possesses two interesting chemical features: a “bow-tie” spirocyclopropyl group that made a significant impact on potency and overall properties [...]

Drug lipophilicity is a core property that contributes to drug solubility, permeability, metabolic disposition, and other key properties. Increasing lipophilicity can often lead to increased affinity in relevant biological assays due to the hydrophobic nature of many protein binding pockets,  but this may also increase promiscuity to [...]

The real magic happens when chemists can integrate computational models into their assay cascades, thanks to trust in their predictions. To get there, grounding computational predictions in physics and experimental reality makes all the difference. In this article, Abba E. Leffler, Ph.D. from Schrödinger tells us about: How to make [...]

In this article, we highlight the importance of p K a values in medicinal chemistry and drug discovery and provide a reference poster of p K a values of common amines’ conjugate bases. Since amines are often a part of marketed drugs, knowledge of their p K a s can provide guidance in the selection of basic moieties to match the desired [...]

The FORUM Pharmaceuticals CNS-penetrant gamma secretase inhibitor and preclinical candidate, FRM-024 , is an advanced example of the use of an oxadiazine as an amide isostere . While amide isosteres are frequently proposed, it is often difficult to implement them beyond basic heterocyclic replacements. A benzofuran structural alert was [...]

Modern hit-finding technologies are incredible. Dean Brown and Jonas Bostrom at AstraZeneca have a very nice review out summarizing the hit-finding strategies for 66 clinical candidates published from 2016-2017. Some highlights include a clinical candidate from DNA-encoded libraries at GSK, the discovery of an RNA-binding drug candidate by [...]