![]() ![]() ![]() (10) Similarly, agents that target a subset of CDKs are being evaluated in a range of other clinically defined segments. For example, the highly selective CDK4/6 inhibitor palbociclib has been approved for the treatment of ER-positive, HER2-negative breast cancer, while abemaciclib, palbociclib, and ribociclib are in phase III clinical trials to treat advanced breast cancer in which signaling through the CDK4/6-retinoblastoma axis is critical. (3) However, an appreciation of the roles played by specific CDKs in sustaining signaling through dysregulated pathways that drive particular cancers is leading to more stringent patient selection and correspondingly improved efficacy. (5-9) The clinical development of CDK inhibitors as antitumor agents was originally hampered by poor kinase selectivity, particularly within the CDK family, and uncertainty as to which CDK constitutes the most appropriate therapeutic target. In this context, a large number of ATP-competitive inhibitors have been evaluated. Pharmacological inhibition of CDK family members is a potential therapeutic approach for the treatment of cancer. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2. ![]() 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 compound is therefore a useful tool for studies of cell cycle regulation. Most impressive was 4-((6-(-3-yl)-9 H-purin-2-yl)amino) benzenesulfonamide ( 73) that exhibited high potency toward CDK2 (IC 50 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC 50 86 μM). 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. 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. ![]()
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