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#KRas #JMedChem

We discovered a number of analogues which formed a bidentate interaction with Asp38, pushing Switch I into a completely new orientation with Glu37 out of the pocket! Interestingly, some of these compounds seem to show a slight preference for binding to the active forms of RAS c.f. inactive.

By swapping out the phenol for an amino-pyridine, we were able to find compounds which did just that. Despite the affinity towards the inactive forms of RAS dropping off with this series, they maintained their single digit micromolar affinity to the active forms, making them roughly equipotent.

As well as the strategy of designing compounds that fit more readily into the constraints of this smaller pocket in the active form, we considered an other approach. Can we push deeper into this site, and pick up interactions with a different residue, recovering the affinity towards the active form?

We think this may be due to the preferred orientation of the Glu37 residue in this active form – despite being distal to the nucleotide binding site, in a number of our ligand-free structures, it seems happier moving into the area occupied by this series:

The big step forward came when we solved the crystal structure of compound A below, which suggested that forming a macrocycle between the amide nitrogen and the one on the benzothiazole ring could constrain our molecules in the bioactive conformation:

Using structure-guided design principles, we were able to optimise these hits, which were shown to bind in the Switch I/II pocket (similar to compounds from the Fesik group, and Boehringer’s BI-2852)

One of the initial aims of our Programme was to establish a fragment-based platform to find hit matter for challenging targets previously considered “undruggable”, such as GTP-ases. From this, we discovered a number of novel, structurally-enabled fragment hits, weakly bound to KRAS: