Citation: Yonghui Sun, Xin Luo, Zimo Yang, Wenxing Lv, Lixia Chen, Hua Li, Yu Rao. Developing potent BTK^C481S PROTACs for ibrutinib-resistant malignant lymphoma[J]. Chinese Chemical Letters, ;2023, 34(6): 107924. doi: 10.1016/j.cclet.2022.107924 shu

Developing potent BTK^C481S PROTACs for ibrutinib-resistant malignant lymphoma

Yonghui Sun ^{a, 1} ,
Xin Luo ^{b, 1} ,
Zimo Yang ^a ,
Wenxing Lv ^a ,
Lixia Chen ^b ,
Hua Li ^{b, c, *,} ,
Yu Rao ^{a, *,}

a.
MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China
b.
Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
c.
Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China

li_hua@hust.edu.cn

yrao@tsinghua.edu.cn

Received Date: 1 May 2022
Revised Date: 17 October 2022
Accepted Date: 18 October 2022
Available Online: 20 October 2022

Figures(6)

Ibrutinib is a first-line treatment drug for B-cell malignancies. However, resistance to ibrutinib has been reported due to BTK^C481S mutation. Although PROTAC strategy is expected to overcome this clinical resistance, it has limitations such as large molecular weight and moderate bioactivity, which restrict its potential clinical application. Herein, we report a new type of potent BTK^C481S-targeting PROTAC degrader. Through design, computer-assisted optimization and SAR studies, we have developed a representative BTK^C481S degrader L6 with a much smaller molecular weight and improved solubility. Notably, L6 demonstrates better BTK degrading activity and lower IC₅₀ value in ibrutinib-resistant cell line than the first-generation BTK degrader P13I. Optimization strategy of L6 provides a general approach in the development of PROTACs targeting BTK and other proteins for future study.
- Drug design,
- Ibrutinib resistance,
- BTK degraders,
- PROTACs,
- B-cell lymphoma
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通讯作者: 陈斌, bchen63@163.com

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沈阳化工大学材料科学与工程学院沈阳 110142

Developing potent BTKC481S PROTACs for ibrutinib-resistant malignant lymphoma

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通讯作者: 陈斌, bchen63@163.com

Developing potent BTK^C481S PROTACs for ibrutinib-resistant malignant lymphoma