Fragments versus CDK4 and CDK6

The cyclin-dependent kinases (CDKs) were some of the earliest protein kinases targeted for drug discovery. They are important for cell-cycle progression, and thus cancer. However, selectivity among the multiple CDK family members has been challenging. In the June issue of ACS Med. Chem. Lett., researchers from Astex and Novartis describe the optimization of a fragment to a selective inhibitor of CDK4 and CDK6.

Astex has been working on CDKs for some time; one of Practical Fragments’ first posts described AT7519, an inhibitor of CDK1, 2, 4, 5, and 9 that is in multiple phase 2 clinical trials. In the new paper, the researchers start with a fairly potent CDK6 hit (fragment A). Crystallography suggested that replacing the pyrrole with a pyridine would provide better vectors from which to grow the fragment, leading to Compound B, which was still active. Growing in two directions then led to Compound 1, and extensive structure-based design led ultimately to Compound 6, which is selective for CDK4 and CDK6 over CDK1 and CDK2. In a panel of 35 additional off-target kinases, the compound displayed IC₅₀ values of 5 micromolar or worse. Compound 6 also showed target modulation in mice and tumor xenograft activity, albeit at fairly high doses.

The authors note that selectivity was a key goal, and that in the course of optimization they were willing to sacrifice potency against their desired targets in order to avoid hitting CDK1 and CDK2. The success of this strategy illustrates again the importance of maximizing ligand efficiency at the outset, as drops in LE can then be used to “pay” for other desirable properties. (Note also that the drop in LLE_AT is not quite as severe as the drop in LE.)

Some enthusiasts have argued that fragments provide a more efficient path to the clinic, and this can certainly be the case, as illustrated by the rapid progress of vemurafenib from fragment to drug. However, the current paper illustrates that advancing fragments can still require considerable resources: with 36 authors on two continents, it is clear that this project was not a walk in the park. It is, however, another illustration of starting with a fragment to develop a useful molecule.