2. Academic Validation
  3. Discovery of a novel molecular glue degrader targeting GSPT1/2 with a non-IMiD-based CRBN binder

Discovery of a novel molecular glue degrader targeting GSPT1/2 with a non-IMiD-based CRBN binder

  • Eur J Med Chem. 2025 Apr 15:291:117642. doi: 10.1016/j.ejmech.2025.117642.
Seulki Park 1,  Akshay D Takwale 2,  Ji-Eun Lee 3,  Namsik Yu 2,  Yong Hyo Kim 2,  Joo Youn Lee 2,  Yong Hee Cho 4,  Jin Hwa Cho 1,  Jeong Hee Moon 5,  Gaseul Lee 6,  Jung-Ae Kim 7,  Jong Yeon Hwang 8,  Jeong-Hoon Kim 9
Affiliations

Affiliations

  • 1 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
  • 2 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606, Republic of Korea.
  • 3 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea; Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
  • 4 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 5 Core Research Facility & Analysis Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
  • 6 Core Research Facility & Analysis Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, 28160, Republic of Korea.
  • 7 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea; Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
  • 8 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: jyhwang@krict.re.kr.
  • 9 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: jhoonkim@kribb.re.kr.
PMID: 40252382 DOI: 10.1016/j.ejmech.2025.117642
Abstract

Targeting undruggable proteins by inducing proximity between E3 Ligase and their substrates has emerged as an innovative strategy for tackling challenging diseases. In this study, we identified a novel GSPT1 degrader, 4a (KMG-1068), through screening of our in-house small molecule library. Treatment with 4a demonstrated significant anti-proliferative activity across multiple cell lines, which was diminished by co-treatment with MLN4924, suggesting the involvement of the Cullin-containing complex. Quantitative proteomic analysis indicated that 4a predominantly induces the degradation of GSPT1/2. We further validated that 4a-mediated GSPT1/2 degradation is dependent on both CUL4 and CRBN. Moreover, 4a forms a ternary complex with CRBN and GSPT1/2, albeit with weaker binding affinity compared to reported GSPT1 Molecular Glues. BRET assays and competition assays with pomalidomide demonstrated that 4a binds to the C-terminal IMiD binding site of CRBN, leading to the degradation of GSPT1. Despite lacking the characteristic glutarimide moiety present in Other CRBN-based molecular glue degraders, 4a interacts effectively with the IMiD binding site of CRBN. Structural characterization through analog synthesis further underscored the importance of specific structural features for CRBN engagement, GSPT1/2 degradation, and anti-proliferative effects, establishing 4a as a promising novel GSPT1/2 degrader with significant therapeutic potential.

Keywords

CRBN; GSPT1; GSPT2; IMiD; KMG-1068; Molecular glue.

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