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

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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Publication Details

Journal
JACS Au
Published
2024-11-08
DOI
https://doi.org/10.1021/jacsau.4c00762
Citations
9
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
4.09

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article

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

Jiayi Lu, Wenchao Lu, Xiaozhong Peng, Ping Yang et al.
9 citations
JACS Au
Acute Myeloid Leukemia Research
4.09
article

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

Jiayi Lu, Wenchao Lu, Xiaozhong Peng, Ping Yang, Qiangqiang Han, Baishan Jiang, Lixin Zhou, Xi Chen, Yuhang Liu, Lü Chen, Shuo Zhang, Yanli Sun, Lanlan Li, Zhixiang Guo, Weiye Lin, Jing Yang, Zhe Wang, Taiting Shi, Linhui Cao, Lu Huang
article en
9 citations

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.

JACS AuVol. 4(11)
Tongji University (CN), Northeastern University (US), Guizhou University (CN), Yantai University (CN), Anhui Medical University (CN), Wenzhou Medical University (CN), First Affiliated Hospital of Wenzhou Medical University (CN), ShanghaiTech University (CN), Wuhan University (CN), Zhongnan Hospital of Wuhan University (CN), First Affiliated Hospital of Anhui Medical University (CN), Tongji Hospital (CN)
Wenzhou Medical University, Yantai University, Anhui Medical University, Science and Technology Commission of Shanghai Municipality, Guizhou University, Tongji University, Wuhan University, ShanghaiTech University, Zhongnan Hospital of Wuhan University, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities
Good health and well-being
Openalex Percentile: Top 5%
Acute Myeloid Leukemia Research
4.09
DOIOpen Access PDFOpenAlex
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