Design, synthesis, and evaluation of a novel protein degrader FPFT-2216

For multiple myeloma (MM), various modalities of therapeutic drugs have been approved in recent years, and treatment outcomes for MM have greatly improved, but unmet medical needs still exist and new therapeutic drugs are needed. With the aim of developing a therapeutic drug for MM that has a scaffold different from the protein degrader immunomodulatory drugs (IMiDs), exploratory research was performed using the highly useful Huisgen cycloaddition reaction, and a novel lead compound 3-(4-(thiophen-3-yl)- 1H -1,2,3-triazol-1-yl)piperidine-2,6-dione (FPFT-2127) was discovered. Optimization studies identified FPFT-2216, which exhibited stronger antitumor activity against MM than existing thalidomide derivatives. Furthermore, FPFT-2216 showed a synergistic combination effect with Daratumumab (Dara), a standard treatment for MM. • Molecular glue can inhibit a target protein via the ubiquitin-proteasome pathway. • FPFT-2127 ( 1 ) has a novel structure “thiophene-1,2,3-triazole” as a molecular glue. • FPFT-2216 ( 6 ), which was discovered by optimizing ( 1 ), shows potent anti-tumor activities against multiple myeloma.