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  3. Design and evaluation of anaplastic lymphoma kinase degraders using a covalent fumarate handle

Design and evaluation of anaplastic lymphoma kinase degraders using a covalent fumarate handle

  • Bioorg Med Chem Lett. 2025 Mar 1:117:130075. doi: 10.1016/j.bmcl.2024.130075.
Namsik Yu 1,  Ji-Eun Lee 2,  Seulki Park 3,  Su Kyeong Yun 4,  Do Hyun Ryu 5,  Jung-Ae Kim 6,  Jeong-Hoon Kim 7,  Jong Yeon Hwang 8
Affiliations

Affiliations

  • 1 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Chemistry, Sungkyunkwan University, Jangan-Gu, Suwon, Republic of Korea.
  • 2 Aging Convergence 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.
  • 3 Disease Target Structure 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 34114, Republic of Korea; Department of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 5 Department of Chemistry, Sungkyunkwan University, Jangan-Gu, Suwon, Republic of Korea.
  • 6 Aging Convergence 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; Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea. Electronic address: jungaekim@kribb.re.kr.
  • 7 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Republic of Korea; Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea. Electronic address: jhoonkim@kribb.re.kr.
  • 8 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea. Electronic address: jyhwang@krict.re.kr.
PMID: 39681169 DOI: 10.1016/j.bmcl.2024.130075
Abstract

Targeted protein degradation has emerged as a novel therapeutic paradigm in drug discovery. Despite the FDA approval of anaplastic lymphoma kinase (ALK) inhibitors, the pursuit of compounds with enhanced potency and prolonged efficacy remains crucial to mitigate inevitable adverse effects. In this context, we endeavored to develop ALK degraders utilizing FDA-approved ALK inhibitors-crizotinib, ceritinib, brigatinib, and alectinib-as ALK Binders, along with 4-methoxyphenylfumarate as a covalent handle to bind to RNF126 E3 Ligase. Among the synthesized compounds, dALK-3-derived from brigatinib-efficiently induced the proteasomal degradation of EML4-ALK and exhibited a 10-fold superior anti-proliferative effect on H3122 cells compared to brigatinib. However, the enhanced anti-proliferative activity of dALK-3 was found to be independent of RNF126, a presumed potential E3 Ligase, suggesting the need for investigation of Other components within the ubiquitin-proteasome system. Our findings further support the potential application of the fumarate moiety as a binder for E3 Ligases in targeted protein degradation.

Keywords

Anaplastic lymphoma kinase; Brigatinib; Molecular glue degrader; RNF126 E3 ligase; Targeted protein degradation.

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