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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-l...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927403/ https://www.ncbi.nlm.nih.gov/pubmed/33658076 http://dx.doi.org/10.1186/s13321-021-00492-5 |
Sumario: | 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] |
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