EPIKIN: EPIgenetic marks for unbiased, high content functional profiling of clinical KINase inhibitors.

Protein kinases are among the most important drug targets. More than 500 kinase are implicated in the control of most cellular process and dysregulation of their activity is linked to a large number of diseases, including cancer and inflammatory disorders. It is estimated that Clinical Kinase Inhibitors (CKIs) account for about 30% of the overall drug development efforts in the world.

Most CKIs are intrinsically promiscuous multi-target drugs, therefore able to target multiple kinases. The simultaneous inhibition of multiple kinases and downstream effectors may enhance therapeutic effects but, at the same time, is also expected to increase risk and extent of off-target effects. A major challenge in the development of CKIs is the lack of high-content and unbiased functional profiling approaches in current screening platforms. These factors result in a high attrition rate, with 90% of CKIs clinical trials failing, and limited use of each of these drugs despite their potential to target multiple pathways.

EPIKIN represents an innovative platform integrating experimental, computational and Artificial Intelligence-based approaches for a functional profiling of CKIs’ effects in living cells. Such platform is based on high-throughput and genome-wide measurement of the genomic distribution of chromatin modifications upon treatment with CKIs for an unbiased, high-content readout of their functional effects on cell functions. The resulting unbiased high-content data are integrated and analyzed through computational and machine learning approaches. As proof-of-concept data, the EPIKIN workflow enabled the identification of Midostaurin, an inhibitor of the kinase FLT3 used in therapy of leukemias, as a potent inhibitory of the TBK1 kinase, a central regulator of immune responses.

Applications: - Platform employable in the early clinical pipeline to guide decision making process. - Repurposing platform for approved/failed CKIs identifying new targets and new clinical applications.

Advantages: - Stand-alone platform providing ad hoc experimental and computational pipeline with an in-depth know-how. - Epigenome-centered approach providing unprecedented high-resolution view of CKIs’ functional effects.

 Key Publications:
Gualdrini et al. Mol Syst Biol. 2024. doi: 10.1038/s44320-024-00040-x.