Fragments vs MAT2a: a chemical probe

As many of us know all too well, traditional methods to treat cancer often result in severe and even intolerable side effects. An emerging, gentler approach is based on synthetic lethality: targeting a protein that is essential only in certain cancer cells but not in normal cells. One prominent target is MAT2a, one of two human methionine adenosyltransferases. We’ve written previously about AG-270, a fragment-derived MAT2a inhibitor that entered the clinic. AstraZeneca has also pursued this target, as we discussed here. In a new J. Med. Chem. paper, Stephen Atkinson, Sharan Bagal, and their AstraZeneca colleagues describe a new chemical probe.

 

A differential scanning fluorimetry (DSF) screen of about 55,000 compounds at 100 µM, nearly a third of which were fragments, resulted in a healthy 1.5% hit rate. Further DSF as well as biochemical testing ultimately delivered compound 8, which is quite potent for a fragment. A crystal structure of the compound bound to MAT2a demonstrated that it bound in the same allosteric site targeted by other compounds. The methoxy group was pointed towards a couple backbone carbonyl oxygen atoms, and adding a couple fluorine atoms created a weak hydrogen bond donor with a satisfying 50-fold boost in potency.

 

Adding a hydrogen bond acceptor (compound 12) slightly reduced potency but also decreased lipophilicity. Further inspection suggested opportunities for fragment growing, and free energy perturbation (FEP) calculations suggested that adding the methoxyphenyl group of compound 15 would be fruitful. This turned out to be the case, and further optimization led to AZ’9567. The paper provides plenty of meaty medicinal chemistry, with significant efforts focused on reducing lipophilicity and clearance. FEP was used extensively during the design process, and a retrospective analysis found a good correlation between predicted and measured affinity.

 

AZ’9567 was studied in considerable detail. It has excellent oral bioavailability and good pharmacokinetics in both mice and rats. The compound does not significantly inhibit cytochrome P450 enzymes or hERG and is reasonably clean against a panel of 86 off-targets. The main liability is poor solubility, a problem also faced by AG-270. Nonetheless, the AstraZeneca researchers were able to develop a liquid formulation.

 

The paper compares AZ’9567 with AG-270, showing that both compounds are potent in biochemical assays as well as against cell lines in which MAT2a is essential. A mouse xenograft model with AZ’9567 showed considerable and sustained tumor growth reduction.

 

Unfortunately, AG-270 is no longer in clinical development, and there is no mention of a MAT2a inhibitor in the AstraZeneca pipeline. Nonetheless, having a second well-characterized chemical probe will be useful for further characterizing the biology of MAT2a and assessing whether it will be a productive drug target.