Fragments in the clinic: LYS006

Practical Fragments’ first list of fragment-derived clinical compounds, published in 2009, listed just 17 molecules. The current count is approaching 50. One of the original compounds, DG-051, targeted the enzyme leukotriene A₄ hydrolase (LTA4H). That molecule did not advance, but in a recently published J. Med. Chem. paper Christian Markert and colleagues at Novartis describe the discovery of a superior clinical compound.

 

LTA4H catalyzes the rate-determining step in the biosynthesis of leukotriene B₄, a pro-inflammatory lipid implicated in multiple diseases. The researchers performed a differential scanning fluorimetry (DSF) screen of the enzyme against a library of 1800 fragments, 350 of which had been selected by in silico screening. This exercise yielded 14 hits that stabilized the protein against thermal denaturation, including compounds 1 and 2. Crystallography revealed that they both bind in the hydrophobic substrate pocket.

 

Merging compounds 1 and 2 led to compound 3, with low nanomolar potency. However, this lipophilic amine had poor stability in rat liver microsomes and also inhibited hERG and a couple CYP450s. Adding a carboxylic acid (compound 13) fixed these problems, though the molecule did bind to the dopamine transporter and had low solubility. Interestingly, the two enantiomers of compound 13 have very similar affinities, and crystallography revealed they could each bind in a similar fashion. Further optimization of the lipophilic tail ultimately led to LYS006. The crystal structure of this molecule overlays nicely with the initial fragments.

 

Much of the paper is devoted to characterization of LYS006, which appears to be a remarkably selective molecule. It does not bind or inhibit > 150 GPCRs, hERG, CYP450s, or a panel of metalloproteases. Oral bioavailability and pharmacokinetics are good in mouse, rat, and dog, and the molecule achieves essentially complete target inhibition at low nanomolar plasma levels. Moreover, LYS006 showed efficacy in preclinical efficacy studies. The drug is currently in four phase 2 clinical trials for ulcerative colitis, inflammatory acne, NASH, and hidradenitis suppurativa. (One of these began in 2018, yet only now are we finding out the origins of LYS006; this illustrates the difficulty of maintaining an up-to-date list of fragment-derived drugs.)

 

This is a beautiful drug discovery story with several lessons. First, like AZD5363 and many other examples, enzymatic potency was achieved relatively quickly; the bulk of the effort was focused on improving other properties. Second, the final molecule is not necessarily “surprising”: it contains the same biaryl-ether pharmacophore found in previous clinical compounds. Yet fragments along with careful medicinal chemistry allowed the researchers to obtain a best-in-class inhibitor.

 

Finally, this effort is a useful reminder that persistence can pay off: although LTA4H has been the target of drug discovery for decades, no inhibitors have yet been approved. Hopefully LYS006 will succeed.