Fragments in the clinic: Navoximod

A good fragment can be a useful starting point for creative scientists, no matter where it comes from. Indeed, we recently described how fragment-derived molecules discovered at one institution were used to discover a clinical compound at another. A similar story from Mario Mautino and collaborators at NewLink Genetics and Genentech has recently appeared in J. Med. Chem.

The researchers were interested in the protein indoleamine 2,3-dioxygenase 1 (IDO1), whose immunosuppressive properties may allow cancer cells to survive and proliferate. They took their starting point from a 2006 publication of a crystal structure of compound 1 bound to IDO1. Structure-based design led to potent molecules such as compound 11, but (not unexpectedly) these phenol-containing molecules tended to have high clearance.

Abandoning the phenols, the researchers instead began rigidifying the series, leading to modest improvements in potency as exemplified by compound 37. Modeling suggested that fragment growing could be productive, and this was confirmed by compound 46.

IDO1 is a heme-containing enzyme, and in fact the imidazole moiety of compound 1 interacts with the heme iron. Other human heme-dependent enzymes include the CYPs, and since these are often involved in metabolizing drugs, it is important to avoid inadvertently inhibiting them. The researchers spent considerable effort further optimizing their molecules for potency, selectivity against CYPs, and metabolic stability. This is described in extensive detail – it makes for an excellent case study in lead optimization. (The separation of stereoisomers and absolute assignment is an impressive piece of work.) Ultimately they arrived at navoximod (NLG-919 or GDC-0919), which showed activity in mouse xenograft models and suitable properties for oral dosing in humans, and entered the clinic in 2014.

Unfortunately, although several IDO1 inhibitors have entered clinical development, those that have made it to late stage trials have proven disappointingly ineffective. Whether some combination with other drugs or a new biomarker will reinvigorate interest in this target, or whether, like BACE1, a good idea meets an unforgiving reality, remains to be seen. There is still no shortcut to avoid the massively expensive experiment of putting a drug into the clinic to test a therapeutic hypothesis.