Akshay D. Takwale

Korea Research Institute of Chemical Technology

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Jong Yeon Hwang

Korea Research Institute of Chemical Technology

Jeong‐Hoon Kim

Korea Research Institute of Bioscience and Biotechnology

Jin Hwa Cho

Korea Research Institute of Bioscience and Biotechnology

Jeong Hee Moon

Korea Research Institute of Bioscience and Biotechnology

Ga Seul Lee

Korea Research Institute of Bioscience and Biotechnology

Dong-Ho Lee

Korea Research Institute of Chemical Technology

Joo‐Youn Lee

Seoul National University

Yeong Uk Jeon

Korea Research Institute of Chemical Technology

Heung Kyoung Lee

Korea Research Institute of Chemical Technology

Ji Won Kim

Seoul National University

Cooperative Institutions

Korea Research Institute of Chemical Technology

Korea University of Science and Technology

Seoul National University

Korea Research Institute of Bioscience and Biotechnology

Korea Advanced Institute of Science and Technology

Chungnam National University

Pusan National University

Yonsei University

Korea University

Sungkyunkwan University

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Discovery of a Novel Molecular Glue Degrader Targeting Gspt1/2 with Non-Imid Based Crbn Binder

Seulki Park Akshay D. Takwale Jieun Lee Nengwei Yu Yong Kim

GLUE

10.2139/ssrn.5108916

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

Bioorganic Chemistry (2022)

Akshay D. Takwale Eun Yeong Kim Yerin Jang Dong-Ho Lee Seulgi Kim

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.

Cereblon

10.1016/j.bioorg.2022.105923

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Citations (9)

Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras

European Journal of Medicinal Chemistry (2020)

Akshay D. Takwale Seunghyun Jo Yeong Uk Jeon Hyung Soo Kim Choong Hoon Shin

Cereblon

Proteolysis

Protein Degradation

10.1016/j.ejmech.2020.112769

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