Cyclin-Dependent Kinase (CDK) Inhibitors: Structure–Activity Relationships and Insights into the CDK‑2 Selectivity of 6‑Substituted 2‑Arylaminopurines

Purines and related
heterocycles substituted at C-2 with 4′-sulfamoylanilino
and at C-6 with a variety of groups have been synthesized with the
aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents
that favor competitive inhibition at the ATP binding site of CDK2
were identified and typically exhibited 10–80-fold greater
inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1′-biphenyl]-3-yl)-9H-purin-2-yl)­amino) benzenesulfonamide (73)
that exhibited high potency toward CDK2 (IC50 0.044 μM)
but was ∼2000-fold less active toward CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies
of cell cycle regulation. Crystal structures of inhibitor–kinase
complexes showed that the inhibitor stabilizes a glycine-rich loop
conformation that shapes the ATP ribose binding pocket and that is
preferred in CDK2 but has not been observed in CDK1. This aspect of
the active site may be exploited for the design of inhibitors that
distinguish between CDK1 and CDK2.