Fragments vs DHODH

Rapidly proliferating cancer cells require a steady supply of nucleic acids, and cutting that off is a potential therapy. The enzyme dihydroorotate dehydrogenase (DHODH), which is important for pyrimidine synthesis, is thus an interesting drug target. In a recent ACS Med. Chem. Lett. paper, Lindsey DeRatt, Scott Kuduk, and colleagues at Janssen describe their approach.

 

The researchers had previously used virtual screening and structure-based drug design to develop compound 1, which is potent in both biochemical and cell-based assays. However, the molecule is highly effluxed by P-glycoprotein, which can limit both oral bioavailability and brain penetration. Thus, they turned to fragments.

 

An SPR screen (about which sadly no details are provided) yielded compound 2, and crystallography revealed that the amide carbonyl makes a similar contact to tyrosine 356 (Y356) as does the carbonyl in the triazolone moiety of compound 1. Merging these led to compound 4, which was considerably more potent than compound 2 but much less so than compound 1. However, further optimization led eventually to compound 25. Although less potent in an enzymatic assay than compound 1, compound 25 is equally effective in cells. It also has excellent pharmacokinetics in mice and – importantly – a considerably lower efflux ratio.

 

Interestingly, when the researchers solved the crystal structure of a related molecule bound to DHODH, they found that the carbonyl no longer interacts with Y356 but is instead flipped 180º and interacts with a different residue. The researchers conclude by stating that they are designing new molecules to reengage Y356, which could further improve potency.

 

Several lessons emerge from this brief paper. First, the flipped urea moiety is another reminder that fragments do not always maintain their orientations, as also seen here, here, and here. Second, information from the fragment was used not to improve potency but rather to address other aspects of an existing lead series, as seen here and here. And finally, one could argue that the only critical feature of the fragment remaining in the final molecule is the NH of the urea. But the fragment did cause the researchers to examine their molecules from a different perspective, resulting in a better series. Perhaps you could call this an example of fragment-assisted drug discovery. As is so often the case, fragments can inspire new ideas that may otherwise be overlooked.