Fragments vs MCL-1 revisited: on to low nanomolar potency

The protein MCL-1 binds to other proteins to protect cancer cells from apoptosis. Protein-protein interactions have historically been considered difficult, but as we’ve noted previously (here, here, here, and here, for example) fragments have been successfully deployed against this target. A recent paper in J. Med. Chem. provides the latest update from Stephen Fesik and co-workers at Vanderbilt University.

We last highlighted this program in early 2013, when the Fesik lab disclosed a series of mid-nanomolar inhibitors, such as compound 1, derived from fragment merging. In the new paper, they report compound 2 as another fragment identified in the original NMR screen.

NMR-based structural information of this molecule bound to ¹⁵N, ¹³C double labeled MCL-1 revealed a similar binding mode as the previous series, and merging the molecules led to the low nanomolar compound 34, with impressive ligand efficiency. This compound was also >1700-fold selective for MCL-1 over the related protein BCL-x_L and >250-fold selective over BCL-2.

Although compound 34 did show activity in cell lysates, the authors note that it is unlikely to be potent enough to show unambiguous activity in cellular assays. Indeed, researchers at AbbVie and Genentech have recently reported MCL-1 inhibitors that show picomolar activity in biochemical assays but only high nanomolar to low micromolar activity in cells.

Still, this is another nice illustration of the power of fragments – combined with a healthy dose of medicinal chemistry – to tackle a difficult target. Notably, the researchers didn’t have to turn to super-sized fragments. Moreover, the best molecule shown is well within Lipinski space, and there are plenty of avenues for further optimization. It will be fun to watch this story progress.