Type II Kinase Inhibitors Library
ChemDiv’s library of the small molecule type ll kinase inhibitors contains 8,000 compounds.
Type II kinase inhibitors represent a separate class of drugs targeting kinases, a group of enzymes crucial for various signaling pathways within cells. Those inhibitors have distinct mechanisms and advantages in drug discovery, particularly in the treatment of cancers and other diseases where kinase dysfunction is a factor.
Type II kinase inhibitors uniquely bind to the inactive conformation of kinases. Unlike type I inhibitors that target the ATP-binding site in its active conformation, type II inhibitors bind to a site adjacent to the ATP-binding pocket, stabilizing the kinase in its inactive state. Drug of this class bind to an extended ATP site including a back pocket formed by displacement of highly conserved DFG (Asp-Phe-Gly) motif (‘DFG-out’) at the start of the activation segment of the kinase.
By binding to this additional site, type II inhibitors act allosterically, or they cause allosteric kinase inhibition. They often occupy a hydrophobic back pocket that becomes accessible only when the kinase adopts its inactive conformation, thereby blocking the activation of the kinase.
Because type II inhibitors specifically target the inactive form of kinases, which is less conserved than the active form, they can achieve significantly higher specificity. This selectivity potentially reduces the risk of off-target effects and toxicity, which is a potential advantage over type I inhibitors.
Furthermore, type II inhibitors can be effective against mutations that confer resistance to type I inhibitors. Some cancers develop resistance to type I inhibitors by altering the kinase's active site, but these mutations usually do not affect the engagement of the type II inhibitors.
The unique mechanism of action typical of type II inhibitors allows them to target a wider range of kinases, including those not effectively inhibited by type I inhibitors. This expands the potential for developing treatments for a broader range of diseases, in particular various forms of cancer.
The Kinase II inhibitors library is a valuable resource in drug discovery, offering a diverse range of compounds specifically designed to target the inactive conformation of kinases. By focusing on the 'DFG-out' conformation, this library provides a unique opportunity to identify inhibitors that are potentially more specific and less toxic, thereby reducing the likelihood of off-target effects. Additionally, the compounds in this library are particularly useful in overcoming drug resistance mechanisms that often limit the efficacy of traditional kinase inhibitors, thereby expanding the possibilities for developing effective treatments for various diseases, especially cancer.