Structure‐based identification of dual ligands at the A(2A)R and PDE10A with anti‐proliferative effects in lung cancer cell‐lines

Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A(2A) receptor (A(2A)R) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) cell-lines. Thus, finding dual-target compounds, which are simultaneously agonists at the A(2A)R whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand- and structure-based modelling combined with MD simulations (which identified Val(84) displacement as a novel conformational descriptor of A(2A)R activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A(2A)R. Subsequent in-vitro analysis confirmed that these compounds bind to the A(2A)R and exhibit dual-activity at both the A(2A)R and PDE10A. Furthermore, many of the compounds exhibited promising anti-proliferative effects upon NSCLC cell-lines, which directly correlated with the expression of both PDE10A and the A(2A)R. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value. [Image: see text]