Discovery of Unexpectedly Active Group

Discovery of Unexpectedly Active Group

Author: Scott Williams

Sometimes sticking to the unconventional pays off. In their efforts toward inhibitors of cyclin-dependent kinases (CDKs) as a new generation of anticancer drugs, Ulrich Lücking and researchers at the Bayer Research Center, Berlin, Germany, discovered a series of pan-CDK inhibitors based on an aminopyrimidine scaffold.

The first clinical candidate of this collaborative research effort, ZK 304709, failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts addressing the off-target activity profile resulted in the introduction of a sulfoximine group. Interestingly, sulfoximines have limited precedent in medicinal chemistry, and their proposed use was met with a good deal of skepticism at first. However, the sulfoximine series of compounds soon revealed very interesting properties. The result of this effort culminated in the identification of the nanomolar pan-CDK inhibitor BAY 1000394 (pictured), which is currently being investigated in phase I clinical trials.


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