2. Academic Validation
  3. A Selective Small-Molecule c-Myc Degrader Potently Regresses Lethal c-Myc Overexpressing Tumors

A Selective Small-Molecule c-Myc Degrader Potently Regresses Lethal c-Myc Overexpressing Tumors

  • Adv Sci (Weinh). 2022 Mar;9(8):e2104344. doi: 10.1002/advs.202104344.
Ying Xu 1,  Qingfeng Yu 1,  Ping Wang 1,  Zhaoxing Wu 1,  Lei Zhang 1,  Shuigao Wu 2,  Mengyuan Li 1,  Bowen Wu 1,  Hongzhi Li 3,  Haifeng Zhuang 4,  Xuzhao Zhang 1,  Yu Huang 5,  Xiaoxian Gan 2,  Rongzhen Xu 1 6
Affiliations

Affiliations

  • 1 Department of Hematology and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 2 Weben Pharmaceuticals, Hangzhou, 310051, China.
  • 3 Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, 91010, USA.
  • 4 Department of Hematology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310009, China.
  • 5 Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
  • 6 Institute of Hematology, Zhejiang University, Hangzhou, 310009, China.
PMID: 35048559 DOI: 10.1002/advs.202104344
Abstract

MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c-Myc protein has been a challenge for >30 years. Here, WBC100, a novel oral active molecule glue that selectively degrades c-Myc protein over other proteins and potently kills c-Myc overexpressing Cancer cells is reported. WBC100 targets the nuclear localization signal 1 (NLS1)-Basic-nuclear localization signal 2 (NLS2) region of c-Myc and induces c-Myc protein degradation through ubiquitin E3 Ligase CHIP mediated 26S Proteasome pathway, leading to Apoptosis of Cancer cells. In vivo, WBC100 potently regresses multiple lethal c-Myc overexpressing tumors such as acute myeloid leukemia, pancreatic, and gastric cancers with good tolerability in multiple xenograft mouse models. Identification of the NLS1-Basic-NLS2 region as a druggable pocket for targeting the "undruggable" c-Myc protein and that single-agent WBC100 potently regresses c-Myc overexpressing tumors through selective c-Myc proteolysis opens new perspectives for pharmacologically intervening c-Myc in human cancers.

Keywords

WBC100; c-Myc oncoprotein; cancer; proteolysis targeting molecule; targeted therapy.

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