TK22 is a small molecule that selectively erases Endothelial-to-mesenchymal transition (EndMT)-competent endothelial state and reverses experimental pulmonary hypertension, inhibits interphase cell-cycle kinases CDK2/3/4/6 node as well as a pro-mesenchymal node of AMPK-related kinases (NUAK1 and SIK1/2/3) together with PDGFRβ and MLK3.
TK22 is developed by structure-based design as an ATP-competitive CDK5 inhibitor with IC50 of 181 nM (CDK5/p35 complex), docking into the CDK5/p25 ATP-binding pocket.
TK22 reversed TGF-β1-induced EndMT across morphological, proteomic, and functional readouts, normalizing α-SMA, SM22, and Calponin, restoring angiogenic tube formation, abolishing acquired smooth-muscle-like contractility, and returning TGF-β1-driven hyperproliferation to baseline without suppressing normal endothelial growth, in primary murine lung endothelial cells.
TK22 selectively eliminated the EndMT-competent and metabolic-stress subpopulations while leaving the remaining endothelial landscape intact.
TK22 normalized right ventricular systolic pressure, Fulton index, and cardiac function in Su5416/hypoxia rat PH model.