Fragments vs PRMT5/MTA: the runners-up

In January this year we highlighted the discovery of MRTX1719, Mirati’s clinical-stage inhibitor of the PRMT5/MTA complex which is being tested in patients with solid tumors bearing a homozygous MTAP deletion. In a recent article, Chris Smith, Svitlana Kulyk, and collaborators at Mirati and ZoBio discuss some of the other series that came from this campaign. (This article is part of a RSC Med. Chem. special issue on FBDD; more on that early next year.)

 

The researchers note that they chose FBLD “based on timelines” and the fact that they had the capability to “rapidly run a fragment screen.” FBLD is sometimes relegated to second place after other approaches fail, so it is refreshing to see the technique, pushed to the forefront, succeed. Details of the fragment screen are described in the earlier paper; this paper focuses on fragment optimization and elaboration.

 

Of the top 24 fragment hits, five yielded co-crystal structures with PRMT5/MTA. All bound in a similar region and participated in a hydrogen-bond network with the protein as well as van der Waals interactions with MTA. Fragment 2 was structurally unique and was ultimately advanced to MRTX1719, while the other four fragments contained a 2-amino substituent next to an aromatic nitrogen, and these are the focus of this paper. The researchers paid close attention to lipophilic ligand efficiency (LLE) to ensure that increases in potency were being driven by polar interactions rather than hydrophobic interactions that might negatively impact the physicochemical properties of the molecules.

 

Fragment 1 was the most potent, with high nanomolar affinity. Unfortunately, the molecule was not very synthetically tractable. Nonetheless, by merging this fragment with a previously reported PRMT5 inhibitor the researchers were able to obtain low nanomolar compound 9. Interestingly, crystallography revealed that while the fragment maintained its binding mode, the bit taken from the previous molecule bound quite differently than expected.

Fragment 3 was the most lipophilic of the hits, so before diving into serious chemistry the researchers sought to optimize the fragment. This led to compound 13, with lower clogP and improved LLE (as well as LE). Fragment growing quickly led to 150 analogs, with compound 27 showing low nanomolar potency.

 

Fragments 4 and 5, which differ only in the position of a methyl group, were the weakest of the five hits. Like fragment 3 they were also synthetically tractable, and the researchers were able to make 50 analogs, with compound 36 coming in at mid-nanomolar with improved LLE.

 

The paper is a nice case study in fragment- and structure-based design. The use of LLE as an explicit SAR driver is notable, as is the optimization of fragments before beginning growing efforts. The importance of chemical tractability is reflected in the fact that the most potent fragment did not ultimately lead to the clinical compound. It would have been nice to see more discussion on what factors led to the prioritization of the series derived from fragment 2: cell activity, DMPK properties, or other considerations. But at the end of the day the message is that fragments can provide multiple starting points for lead optimization.