Rational design of PIN1 inhibitors for cancer treatment based on conformational diversity analysis and docking based virtual screening.

The parvulin PIN1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1), is the only enzyme capable of isomerizing prolines of phospho-Serine/Threonine-Proline motifs. PIN1 binds to a subset of proteins and plays an essential role in regulating protein function post-phosphorylation control. Furthermore, the activity of PIN1 regulates the outcome of the signalling of proline-directed kinases (e.g. MAPK, CDK, or GSK3) and thus regulates cell proliferation and cell survival. For these reasons, PIN1 inhibitors are interesting since they may have therapeutic implications for cancer. Several authors have already reported that the non-structural point mutation Trp34Ala prevents PIN1 from interacting with its downstream effector proteins. In this work, we characterized PIN1 structurally, intending to explore new inhibition targets for the rational design of pharmacological activity compounds. Through a conformational diversity analysis of PIN1, we identified and characterized a highly specific druggable pocket around the residue Trp34. This pocket was used in a high-throughput docking screening of 450,000 drug-like compounds, and the top 10 were selected for re-docking studies on the previously used conformers. Finally, we evaluated the binding of each compound by thermal shift assay and found four molecules with a high affinity for PIN1 and potential inhibitory activity. Through this strategy, we achieved novel drug candidates with the ability to interfere with the phosphorylation-dependent actions of PIN1 and with potential applications in the treatment of cancer.Communicated by Ramaswamy H. Sarma.

Telomerase regulation: a key to inhibition? (Review).

Telomerase has been recognized as a common factor in most tumor cells, and in turn a distinctive feature with respect to non-malignant cells. This feature has made telomerase a promising target for cancer therapy. Telomerase studies revealed that it is a multi-subunit complex possessing different levels of regulation, including control of expression, phosphorylation state, assembly and transportation to sites of activity. Thus, we emphasize that targeting telomerase expression or activity is not the only way to shorten telomeres, induce cell senescence and apoptosis. Therefore, there are multiple sites capable of allowing the modulation of its enzymatic activity. In the development of strategies based on the regulation of telomerase activity the understanding of the mechanisms regulating their subunits is essential. Based on this, in this review we summarize the current state of knowledge of some regulatory mechanisms of the components of the telomerase complex, and hypothetize their potential therapeutic application against cancer.