Development of Novel Anticancer Agents with a Scaffold of Tetrahydropyrido[4,3-d]pyrimidine-2,4-dione

ONC201 is a small molecular anticancer agent currently in multiple Phase II clinical trials. Based on the pharmacophore of ONC201, a series of small molecular compounds with a core structure of tetrahydropyrido[4,3-d]pyrimidine-2,4-dione were designed and synthesized. Preliminary mechanism studies of these compounds indicated that they can inhibit the phosphorylation of AKT and ERK, induce the dephosphorylation of Foxo3a, and promote the expression of TRAIL and the enhancement of activating transcription factor 4 (ATF4) in PC-3 cells. Structure–activity relationship (SAR) studies indicated that modifications of the substituted groups on the core structure can significantly improve the cellular activities of these compounds. The most potent compounds are over 100 times more potent than ONC201 in inhibition of cell growth in a panel of different types of human cancer cell lines.