Structure-based identification of dual ligands at the A_2AR and PDE10A with anti-proliferative effects in lung cancer...

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_2AR) 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_2AR whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand- and structure-based modelling combined with MD simulations (which identified Val₈₄ displacement as a novel conformational descriptor of A_2AR activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A_2AR. Subsequent in-vitro analysis confirmed that these compounds bind to the A_2AR and exhibit dual-activity at both the A_2AR 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_2AR. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value.