Design and Synthesis of Novel Thieno[3,2-]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 DRUDIT web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2-]quinolines and were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds as promising anticancer agents, with IC 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 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.