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

  • Bioorg Med Chem Lett. 2025 Aug 1:123:130193. doi: 10.1016/j.bmcl.2025.130193.
Yasuyuki Ueda  1 ,  Takashi Ando  1 ,  Yoshiteru Eikyu  2 ,  Takumi Okamoto  1 ,  Hironori Yokoyama  1 ,  Naoshi Kunimura  1 ,  Daiki Kanaoka  1 ,  Shotaro Izuno  1 ,  Mayumi Watanabe  1
Affiliations
  • 1. Department of Scientific Research, Fujimoto Pharmaceutical Corporation, 1-3-40, Nishiotsuka, Matsubara, Osaka 580-8503, Japan.
  • 2. Department of Scientific Research, Fujimoto Pharmaceutical Corporation, 1-3-40, Nishiotsuka, Matsubara, Osaka 580-8503, Japan. Electronic address: [email protected].
PMID: 40127848 DOI: 10.1016/j.bmcl.2025.130193
Abstract

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.

Keywords
Cereblon; IKAROS family zinc finger 1; Molecular glue; Multiple myeloma; Protein degrader.
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