Design and Synthesis of Novel Thieno[3,2-c]quinoline Compounds with Antiproliferative Activity on RET-Dependent Medullary Thyroid Cancer Cells

RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDITonline web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2-c]quinolines 6a-e and 7a-e were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and in vitro evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds 6a-d as promising anticancer agents, with IC50 values in the micromolar range. Further structure-based computational studies revealed a significant capability of the most active compounds to the complex RET tyrosine kinase domain. The interesting antiproliferative results supported by in silico predictions suggest that these compounds may represent a starting point for the development of a new series of small heterocyclic molecules for the treatment of MTC.

Automated summary

RET kinase gain-of-function mutations are the main cause of high aggressiveness and invasiveness of medullary thyroid cancer. Thieno[3,2-c]quinoline compounds were identified as potential RET inhibitors with promising anticancer activity. Further studies revealed the interaction capability of these compounds with the RET tyrosine kinase domain.