23 April 2018

Fragments in the clinic: eFT508

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.

6 comments:

Peter Kenny said...

Hi Dan, as with my comments on your mGluR4 post, I wouldn't regard this as 'true' FBDD (this is most definitely not a criticism) because the starting points are so potent. The compounds are in an excellent place with respect to molecular size and lipophilicity. I'm guessing that 7 has better aqueous solubility than 1 but this hunch is based more on speculation about crystal packing than on lipophilicity or molecular size. With a 60 nM starting point, I'd be happy to trade an order of magnitude of affinity for better physicochemical properties. However, I'm not so sure that I would feel the same way if the affinity was 600 μM.

Dan Erlanson said...

Hi Pete,

Yes, this is something of a judgement call; 60 nM is certainly a dream fragment!

On the other hand, the researchers didn't necessarily know compound 1 would be this potent before they tested it, and it does "look" like a fragment.

Suppose compound 1 came out of an SPR screen of 1500 fragments and was 60 micromolar instead of 60 nanomolar. If the researchers optimized it to eFT508, I don't think anyone would question that this was FBLD. I'm reluctant to say that a molecule can bind too tightly to count as a fragment.

Peter Kenny said...

I see the term fragment as referring to the molecular size of a compound (regardless of affinity or even whether it binds). I'd still call a lipophilic compound a fragment if its molecular size was sufficiently small (even if I considered it too lipophilic or ugly for screening). I see FBLD as referring to a process and it could be argued that the fragment hits (I refuse to call them frits) in the featured study are actually leads. One characteristic of 'classical'(maybe a better term than 'true') FBLD is that the fragment hits have low affinity and you need work hard to extract maximum value from any increases in molecular size (the LE concept in a nutshell). I would regard the featured study as conventional SBDD rather than FBLD although, as mentioned in the previous comment, I don't see this as a criticism of the study in any way.

Dan Erlanson said...

I hear you, but I have two questions.

1) Do you consider compound 1 to be a fragment?
2) What is the highest affinity compound 1 could have for this to be considered "classical" FBLD?

Peter Kenny said...

1) Absolutely. Like I said before, whether not I would call something a fragment is determined entirely by molecular size.
2) I use the term 'classical FBLD' to make the point that conventional optimisation of a fragment sized lead should perhaps not automatically be considered to be FBLD. Generally, I would make the call on a case-by-case basis although it's not clear how important it is to make the distinction.

That said, I don't find labels and cutoffs particularly useful and it's also worth remembering that cutoffs are not always determined by the data. For example, the cutoffs for what is sometimes called the GSK 4/400 rule reflect the manner in which continuous data was categorised prior to analysis. I would guess the cutoffs for the rule of 3 were set before any analysis was performed although it is not clear from the original Ro3 article what this analysis entailed.

Jacekk said...

Published fragments can be good starting points for drug discovery programs indeed. Here is one recent example of a current clinical candidate developed from published fragment: https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01714
While the fragment itself is not novel, the vastness of chemical space led to patentable compounds with optimized properties.