Multiple clinical candidates derived from fragments were described at the recent CHI FBDD Meeting. The story behind one of these has just appeared in J. Med. Chem. in a paper published by Siegfried Reich and colleagues at eFFECTOR Therapeutics.
The researchers were interested in mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2), which appear to be important in tumorigenesis but not normal cells. As Paul Sprengeler described it, they started with a “library” of just six fragments – four from the literature and two designed. (The company began in a law office, so hands-on experiments were initially limited.) Some might ask whether this constitutes FBDD, but in the end it’s not the size of your library that counts, but what you do with it.
All the fragments had good affinity, and the researchers were able to obtain crystal structures of four of them bound to MNK2. Optimization proceeded on all six of the fragments, but compound 1 was considered particularly attractive due to its high ligand efficiency and multiple vectors for growing.
Initially the researchers deconstructed the bicyclic ring to compound 7, which led to a 10-fold loss in potency but reduced the molecular weight and lipophilicity. As they note, “loss of potency in exchange for improved physicochemical properties is an often overlooked yet powerful optimization strategy in medicinal chemistry.” Too often people focus on binding over drug-like properties, so it is refreshing to see smart tradeoffs explicitly acknowledged.
Next, the researchers cyclized the molecule to form a lactam and remove one hydrogen bond donor. This also improved the affinity (compound 10). Replacing the phenyl ring in compound 10 with a pyridone in compound 12 further reduced the lipophilicity and improved the selectivity due to non-covalent interactions between a non-conserved cysteine residue and the heterocyclic ring. More optimization led to eFT508.
In addition to low nanomolar potency against both MNK1 and MNK2 in biochemical and cell-based assays, eFT508 is metabolically stable, permeable, and orally bioavailable in mice, rats, dogs and monkeys. The molecule showed good activity in several mouse xenograft models, and tissue samples revealed reduced phosphorylation of the substrate protein eIF4E, as expected. Unlike the MTH1 story last week, in which a selective chemical probe devalidated the target, the results with eFT508 suggest that inhibiting MNK1 and MNK2 has merit, and the compound is currently in four clinical trials for both solid tumors and lymphoma.
Like the story last week, this program progressed rapidly: just 110 compounds, 30 crystal structures, and 1 year to the development candidate. This turned out to be somewhat lucky, as it took another two years to find an equivalently attractive backup candidate. It is also an excellent example of how a non-selective fragment (a purine, found in ATP!) can be turned into a selective molecule. And finally, this is another nice example of how even a public, generic fragment can lead to an attractive chemical series. There are myriad published fragments bound to legions of targets, and it’s worth keeping these in mind whether or not you have in-house biophysical screening capabilities.