Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders

Xiangbo Yang; Zhijia Wang; Yuan Pei; Ning Song; Lei Xu; Bo Feng; Hanlin Wang; Xiaomin Luo; Xiaobei Hu; Xiaohui Qiu; Huijin Feng; Yaxi Yang; Yubo Zhou; Jia Li; Bing Zhou

doi:10.1016/j.ejmech.2021.113341

Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders

Eur J Med Chem. 2021 Jun 5:218:113341. doi: 10.1016/j.ejmech.2021.113341. Epub 2021 Mar 11.

Authors

Xiangbo Yang¹, Zhijia Wang², Yuan Pei¹, Ning Song³, Lei Xu⁴, Bo Feng⁵, Hanlin Wang⁶, Xiaomin Luo⁷, Xiaobei Hu⁴, Xiaohui Qiu⁴, Huijin Feng⁸, Yaxi Yang⁹, Yubo Zhou¹⁰, Jia Li¹¹, Bing Zhou¹²

Affiliations

¹ Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
² National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China.
³ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
⁴ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁵ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenyang, Liaoning, China.
⁶ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmacy, Fudan University, Shanghai, 201203, China.
⁷ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
⁸ Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁹ Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
¹⁰ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. Electronic address: ybzhou@simm.ac.cn.
¹¹ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenyang, Liaoning, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China. Electronic address: jli@simm.ac.cn.
¹² Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address: zhoubing@simm.ac.cn.

PMID: 33780898
DOI: 10.1016/j.ejmech.2021.113341

Abstract

SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC₅₀ of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation.

Keywords: CRBN; E3 ubiquitin ligase; Proteolysis targeting chimera (PROTAC); SHP2 degradation; Thalidomide-based heterobifunctional molecules.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Thalidomide / chemical synthesis
Thalidomide / chemistry
Thalidomide / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Enzyme Inhibitors
Small Molecule Libraries
Thalidomide
PTPN11 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11