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  3. Structure-activity relationship analysis of novel GSPT1 degraders based on benzotriazinone scaffold and its antitumor effect on xenograft mouse model

Structure-activity relationship analysis of novel GSPT1 degraders based on benzotriazinone scaffold and its antitumor effect on xenograft mouse model

  • Bioorg Chem. 2022 Oct:127:105923. doi: 10.1016/j.bioorg.2022.105923.
Akshay D Takwale 1,  Eun Yeong Kim 1,  Yerin Jang 2,  Dong Ho Lee 2,  Seulgi Kim 2,  Yuri Choi 2,  Jin Hwan Kim 1,  Da Yeon Lee 3,  Yeongrin Kim 1,  So Myoung Lee 2,  Heung Kyoung Lee 2,  Hye Jin Nam 2,  Joo-Youn Lee 2,  Jin Hwa Cho 4,  Jeong Hee Moon 4,  Ga Seul Lee 5,  Jeong-Hoon Kim 6,  Pilho Kim 1,  Chi Hoon Park 7,  Jong Yeon Hwang 8
Affiliations

Affiliations

  • 1 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.
  • 2 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 305-606, Republic of Korea.
  • 3 College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 4 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
  • 5 Disease Target Structure Research 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.
  • 6 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Department of Bioscience, University of Science and Technology, Daejeon 34113, Republic of Korea.
  • 7 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: [email protected].
  • 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: [email protected].
PMID: 35717803 DOI: 10.1016/j.bioorg.2022.105923
Abstract

Molecular glue degraders, such as lenalidomide and pomalidomide, bind to Cereblon (CRBN) E3 Ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure-activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone. As a result, we identified 34f (TD-522), which exhibits strong anti-proliferative effects in both KG-1 (EC50 = 0.5 nM) and TMD-8 (EC50 = 5.2 nM) cell lines. Compound 34f effectively induced GSPT1 degradation with a DC50 of 0.269 nM and Dmax of >95 % at 10 nM concentration in KG-1 cells. An in vivo xenograft study showed that compound 34f effectively suppressed TMD8-driven tumor growth, suggesting a potential role in the development of novel GSPT1 degraders.

Keywords

Benzotriazinone; GSPT1; Molecular glue degrader; TD-106; Targeted protein degradation.

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