2. Academic Validation
  3. Development of Oral, Potent, and Selective CK1α Degraders for AML Therapy

Development of Oral, Potent, and Selective CK1α Degraders for AML Therapy

  • JACS Au. 2024 Nov 8;4(11):4423-4434. doi: 10.1021/jacsau.4c00762.
Lu Huang 1 2,  Lu Chen 3,  Lu Chen 2,  Bo Peng 2,  Lixin Zhou 4,  Yanli Sun 2,  Taiting Shi 2 5,  Jiayi Lu 6,  Weiye Lin 2 7,  Yuhang Liu 2 8,  Linhui Cao 2 8,  Lanlan Li 2 9,  Qiangqiang Han 10,  Xi Chen 10,  Ping Yang 1,  Shuo Zhang 1,  Zhe Wang 1,  Jing Yang 4,  Zhixiang Guo 1,  Baishan Jiang 3,  Wenchao Lu 2
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, China.
  • 2 Lingang Laboratory, Shanghai 200031, China.
  • 3 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 4 Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 5 Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 6 College of Science, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
  • 7 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
  • 8 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 9 Institute of Entomology, The Provincial Special Key Laboratory for Development and Utilization of Insect Resources, Guizhou University, Guiyang 550025, China.
  • 10 SpecAlly Life Technology Co., Ltd., Wuhan 430075, China.
PMID: 39610741 DOI: 10.1021/jacsau.4c00762
Abstract

Molecular glue degraders (MGDs) are proximity-inducing agents that mediate the cooperative interaction between a target protein and an E3 Ligase, introducing an additional layer of specificity beyond that afforded by traditional small molecules. Historically, Molecular Glues that stabilize protein-protein interactions were often discovered serendipitously. In this study, we leveraged the reprogramming potential of Cereblon (CRBN)-based ligands and conducted a CRBN-dependent proliferation screen to identify CRBN-based MGDs capable of inducing the degradation of proteins essential for cell viability. Through our screening and subsequent medicinal chemistry optimization, we identified dCK1α-1 as a potent and selective CK1α-targeting molecular glue degrader. Furthermore, we synthesized an orally active derivative, dCK1α-2, with enhanced pharmacokinetic properties, which exhibited pronounced degradation activity and demonstrated efficacy in mouse models following oral gavage. These findings indicate that phenotypic drug discovery campaigns, in combination with chemically distinct CRBN ligand libraries, can accelerate the development of therapeutically relevant MGDs. Furthermore, the development of dCK1α-1 and dCK1α-2 provides new therapeutic options for cancers with functional p53 signaling and offers valuable chemical tools for future investigations into the role of CK1α.

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