On The Cover

Superposition of the X-ray structures of aminoimidazo[1,2-a]pyridine (green carbons) and ATP (magenta carbons) bound to CDK2 (grey tube). The imidazopyridine moiety within the inhibitor occupies the same site as the ATP adenine. N-1 of the imidazopyridine acts as a hydrogen bond acceptor to the backbone amine NH of Leu83 and the amino group acts as a hydrogen bond donor to the backbone carbonyl of Leu83. The structure-based design approach directed the evolution of a chemical scaffold yielding potent CDK2 inhibitors. These inhibitors selectively inhibited the CDK2 dependent phosphorylation of Rb and induced caspase-3 dependent apoptosis in HCT116 tumor cells. For details, see Hamdouchi et al. in this issue.