In silico lead optimization and synthesis of a new series of thieno[3,2-c]quinoline with antiproliferative activity on RET-dependent medullary thyroid cancer cells

Abstract

RET kinase gain-of-function mutations represent the main cause of the high aggressiveness, invasiveness, and resistance of medullary thyroid cancer (MTC). Selective inhibition of the mutated isoforms of RET kinase may represent a turning point for the treatment of this endocrine neoplasia. To this end, we previously developed the thieno[3,2-c]quinoline compounds 1a-e (Figure 1) as new potential inhibitors of RET kinase, which showed promising antiproliferative activity (IC50 of 3 μM) against the particularly aggressive MTC cell line TT (RETC634R). Based on these results, in the present work, we performed a lead optimization process by in silico screening of a novel in-house database of molecules with appropriately substituted thieno[3,2-c]quinoline scaffold, to identify more potent RET-targeting thyroid anticancer agents with improved pharmacokinetic properties. Compounds 2a-l, with a hydrophilic imidazole on the side-chain moiety (Figure 1), proved to be the most interesting, highlighting stronger and tighter interactions with the target protein, and a more favorable orientation towards the catalytic site. The selected compounds were successfully synthetized and spectroscopically characterized. The ongoing in vitro biological testing will allow us to compare the antiproliferative results obtained so far and to further investigate the selective inhibitory activity against RET-634R.