Abstract
Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A2A receptor (A2AR) 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 A2AR 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 A2AR activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A2AR. Subsequent in-vitro analysis confirmed that these compounds bind to the A2AR and exhibit dual-activity at both the A2AR 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 A2AR. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value.
Highlights
Cyclic adenosine monophosphate is a second messenger that has a major role in transduction and cell signaling in several pathways and biological systems [1]. cAMP elevation may be achieved via the activation of the adenylate cyclases by Gs proteins, and the inhibition of cAMP-degrading phosphodiesterases [2], and has been shown to inhibit proliferation of several cancer cell types
Method for selecting triazoloquinazolines as candidates for dual ligand activity at A 2AR and phosphodiesterase 10A (PDE10A) Triazoloquinazolines were identified by Kalash et al as a compound series that showed the highest frequency of prediction as binders at the A2AR and PDE10A by ligandand structure-based approaches (Fig. 1a) [33]
Dual PDE 10A inhibition and A 2AR agonism is anti‐proliferative in Lung carcinoma cells Having established that the compounds 1–5 appear to have dual activity in CHO-KI cells where the A 2AR was over expressed we extended our studies to a series of lung carcinoma cells: two lung squamous cell carcinomas (LUSC): LK-2 and H520, and two lung adenocarcinoma cells (LUAC): H1563 and H1792, which express differing levels of the four adenosine receptor subtypes and PDE10A (Fig. 7a)
Summary
Cyclic adenosine monophosphate (cAMP) is a second messenger that has a major role in transduction and cell signaling in several pathways and biological systems [1]. cAMP elevation may be achieved via the activation of the adenylate cyclases by Gs proteins, and the inhibition of cAMP-degrading phosphodiesterases [2], and has been shown to inhibit proliferation of several cancer cell typesTwo key modulators of intracellular cAMP are the adenosine A2A receptor (A2AR) and the phosphodiesterase 10A (PDE10A), which are often co-expressed in different amounts across NSCLC cell-lines. PDE10A is overexpressed in lung adenocarcinoma, and its inhibition was found to suppress growth [9], demonstrating a correlation between the levels of overexpression and survival [10] This makes these systems interesting avenues of investigation for relating the amount of co-expression of these two protein targets and their ability to elevate cAMP as well as induce anti-proliferation in these cell-lines. The use of multitarget ligands have demonstrated beneficial effects on Alzheimer’s and Parkinson’s disease [12, 13] Combining this approach in single dual-targeted compounds at the A2AR and PDE10A could be explored as a novel anti-proliferative strategy for adenocarcinoma and squamous carcinoma cell-lines
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