2. Academic Validation
  3. Design, synthesis and biological evaluation of novel quinazolinone derivatives as CRBN E3 ligase modulators

Design, synthesis and biological evaluation of novel quinazolinone derivatives as CRBN E3 ligase modulators

  • Eur J Med Chem. 2023 Feb 5:247:115016. doi: 10.1016/j.ejmech.2022.115016.
Linyi Liu 1,  Renhong Sun 2,  Haixia Liu 3,  Chaowei Ren 4,  Yuedong Zhou 2,  Xing Qiu 5,  Ying Kong 4,  Biao Jiang 6,  Xiaobao Yang 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. Electronic address: [email protected].
  • 2 Gluetacs Therapeutics (Shanghai) Co., Ltd., Building 20, Lane 218, Haiji Road 6, Pudong District, Shanghai, 201306, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
  • 5 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: [email protected].
  • 7 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; Gluetacs Therapeutics (Shanghai) Co., Ltd., Building 20, Lane 218, Haiji Road 6, Pudong District, Shanghai, 201306, China. Electronic address: [email protected].
PMID: 36577219 DOI: 10.1016/j.ejmech.2022.115016
Abstract

CRBN E3 Ligase modulators, also anteriorly called immunomodulatory drugs (IMiDs), exhibit excellent pharmacological activity by degrading Cereblon (CRBN) associated multiple substrates and have become an important field for drug development. These modulators such as Thalidomide, Lenalidomide and CC-122 abduct CRBN to adhere to IKZF1/3 and Other neosubstrates, and then induce the degradation of these substrates, thus retarding the further development of related diseases. Herein, we reported a series of CC-122 derivatives that inhibit the proliferation of hematological malignant tumor cell lines. Studies further confirmed that several derivatives which exhibit strong anti-proliferation effect induce the significant degradation of IKZF1/3. In addition, we found that the best compound 14 (SIAIS355035) exhibits better degradation activity and better anti-proliferation activities than CC-122, especially in diffuse large B lymphoma cell lines. Moreover, the PK properties of compound 14 are pretty promising with excellent oral bioavailability. These results clarified the SAR of CC-122 derivatives preliminarily and suggested that compound 14 has great value for further studies as an ideal novel CRBN E3 Ligase modulation drug.

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