Returning to the discussion of fragment-derived compounds that have made it into the clinic, researchers at Astex have published a nice account of the discovery of AT9283, an Aurora kinase inhibitor, in the latest issue of J. Med. Chem. The compound is in phase I testing for the treatment of solid tumors and in phase I/II testing for hematological malignancies.
While pursuing CDK inhibitors, an effort that yielded the clinical compound AT7519 (as highlighted in August last year), Astex researchers discovered that some of their pyrazole-benzimidazoles were potent and highly ligand-efficient Aurora A inhibitors. This illustrates that Nobel laureate James Black’s famous dictum, “the most fruitful basis of the discovery of a new drug is to start with an old drug,” applies to fragments as well – especially when going after kinases.
Crystallography revealed the binding modes of Compounds 5 and 7 (above) to Aurora A, and structure based design suggested adding a morpholine group to improve potency (as well as solubility). This did improve cell potency, but the resulting molecules exhibited very high plasma protein binding. A further series of structure-guided SAR studies succeeded in replacing the phenyl amide with a cyclopropyl urea, resulting in the highly potent and less lipophilic AT9283. This molecule inhibits both Aurora A and B and shows low nanomolar cellular activity consistent with inhibition of Aurora B. It also shows a clean CYP profile, good solubility, and exhibits significant tumor growth inhibition in mouse xenograft models.
Perhaps unsurprisingly given the molecule’s origins, AT9283 hits a number of other kinases too. Some of these, such as JAK2, Flt-3, and the Abl T315I mutant, are attractive cancer targets in their own right. Indeed, the fact that the molecule binds exclusively in the ATP-binding pocket allows it to inhibit kinases, such as Abl(T315I), that are resistant to many adaptive-pocket binding inhibitors such as imatinib. However, the molecule also hits more than 20 other kinases with similar potency, which could lead to off-target side effects. That said, specificity may not be everything it was once thought to be: sales of sunitinib, probably the most non-selective of approved kinase inhibitors, were $627 million for the first nine months of 2008. There is a raging debate in the kinase field over the importance of specificity. It is a debate that only more data will resolve, and AT9283 represents an attractive data point.