A few weeks ago we highlighted the story of eFT508, a clinical MNK1/2 inhibitor derived from a previously published fragment. One of the comments to that post mentioned another example describing a clinical compound against the same targets – also derived from a previously published fragment! This work was recently published in J. Med. Chem. by Kassoum Nacro and a large, multinational group of collaborators from A*STAR and other institutes.
The kinases MNK1 and MNK2 are responsible for phosphorylating and thereby activating eIF4E, a protein that regulates messenger RNA translation. All three proteins are overexpressed in various cancers, particularly blast crisis chronic myeloid leukemia (CML), in which patients stop responding to drugs such as dasatinib. An inhibitor of MNK1/2 could thus potentially resensitize the cancer cells. Moreover, MNK knockout mice are healthy, suggesting that the therapy might be minimally toxic.
The researchers started with a 2010 paper which reported a virtual screen against MNK1; nearly three quarters of the hits were fragments. The A*STAR researchers were particularly attracted to molecules such as ETP-38766, and they used modeling along with a previously reported structure of MNK2 to scaffold-hop to compound 4, with sub-micromolar activity. (MNK1 and MNK2 are closely related, and most reported compounds show similar activity against both; values for MNK1 are given here.)
Building out the molecule further did not do much for biochemical potency but did yield molecules with improved solubility, permeability, and cell-based activity – such as compound 27. Further tweaking of the core and replacement of the metabolically labile methyl piperazine ultimately led to ETC-206, with nanomolar potency in biochemical and cell-based assays. It also shows good pharmacokinetics, is orally bioavailable, and is remarkably selective for MNK1/2: in a panel of 104 kinases screened at 1 µM compound, only one other kinase showed significant inhibition. As expected, the molecule showed little antitumor activity in a xenograft assay when dosed by itself, but significantly improved the activity of dasatinib. Indeed, the molecule has recently entered a phase 1 clinical study in combination with dasatinib.
Several lessons can be drawn from this paper. First, it appears that ETC-206 was derived solely with the aid of modeling, without recourse to experimental structural data for any molecules in the series. Second, both ETC-206 and eFT508 had their origins in fragments previously discovered by others – a reminder that, with the increasing number of publications, you don’t necessarily have to do your own fragment screen in order to do FBLD. (An important corollary is that a fragment does not itself need to be novel to generate patentable chemical matter.) Finally, ETC-206 and eFT508 are both selective MNK1/2 inhibitors but look very different from one another – a reminder that many roads can lead to different clinical candidates for the same target.