Through the looking glass: adventures in kinase inhibitor design and optimization

Developing a viable new drug candidate is difficult. Developing one that is a small molecule kinase inhibitor that binds competitively with respect to ATP with superb selectivity is even more difficult, which makes the design and optimization work described by Jimenez et al. (J. Med. Chem., DOI: 10.1021/jm301465a) particularly remarkable. They took a lead from a high-throughput screen against protein kinase C θ (PKCθ) through a series of optimization steps, culminating in the demonstration of in vivo activity in mice. Having identified and improved the hinge-binding "warhead" at one end of their lead molecule, they proceeded to use structure-based design tools to guide modification of the other end to enhance selectivity over a closely related isoform of the kinase. With that accomplished, they used a series of protection and deprotection maneuvers to modify the central portion of the series scaffold to further enhance potency against the target while also improving pharmacokinetic properties. The project was a success at the preclinical level: oral administration of the ultimate analogue obtained was effective at suppressing interleukin-2 induction in mice.