ChemDiv’s Library of the Allosteric Kinases Inhibitors comprises 26,000 compounds.
Allosteric kinases are a class of enzymes that play a critical role in cell signaling pathways but function differently from typical kinases as they rely on direct binding to ATP binding sites. Unlike conventional kinases, allosteric kinases are regulated through sites distinct from their active sites, known as allosteric sites. Binding at these sites induces conformational changes in the kinase, modulating its activity. This unique mechanism of action makes them particularly important in drug discovery. By targeting allosteric sites, researchers can develop more specific and potentially less toxic therapeutic agents. Such drugs can be characterized by enhanced selectivity as they avoid the highly conserved ATP binding pocket common to many kinases, which is often the target of traditional kinase inhibitors. This specificity not only reduces off-target effects but also helps in overcoming drug resistance, which is a significant challenge in cancer treatment and other diseases where kinase activity is dysregulated. Therefore, allosteric kinase inhibitors, sometimes called modulators, represent a promising frontier in the development of more effective and safer medications.
Small-molecule kinase inhibitors are invaluable targeted therapeutics for treating various human diseases, particularly cancers. While the majority of approved and preclinical small-molecule inhibitors are categorized as type I or II, targeting the ATP-binding pocket of kinases, the significant sequential and structural similarity among ATP pockets makes selectively inhibiting kinases a daunting challenge. Therefore, targeting allosteric pockets outside the highly conserved ATP pocket has been proposed as a promising alternative to overcome the current limitations of kinase inhibitors, including poor selectivity and the emergence of drug resistance. Despite the smaller number of identified allosteric inhibitors compared to those targeting the ATP pocket, the past decade has seen encouraging developments. These include the FDA approval of the first small-molecule allosteric inhibitor, trametinib, in 2013, the advancement of over 10 other allosteric inhibitors in clinical trials, and the emergence of a pipeline of highly selective and potent preclinical molecules. 
The ChemDiv’s Library of Allosteric Kinases Inhibitors, with its comprehensive collection of 26,000 compounds, is specifically designed for drug discovery targeting allosteric kinase sites. This library stands out due to its focus on 135 kinases that have identifiable allosteric pockets, offering a targeted approach to drug design. Significantly, 71 of these kinases are backed by PDB structures, showing their allosteric pockets engaged with small molecules, providing valuable structural insights for researchers.
Moreover, the library is meticulously organized into 795 clusters based on chemical features. This clustering allows for a nuanced and efficient exploration of the chemical space, facilitating the identification of compounds with desired properties and activities. Each cluster contains a significant count of compounds, further enhancing the library's utility in discovering potent and selective allosteric inhibitors.
Examples of the library clusters and main chemical features of compounds offered by this library are provided in a slide deck above, which is freely available for download.
 P. Wu, M. H. Clausen, and T. E. Nielsen, “Allosteric small-molecule kinase inhibitors,” Pharmacol. Ther., vol. 156, pp. 59–68, doi: 10.1016/j.pharmthera.10.002.