Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton’s Tyrosine Kinase for the Treatment of Lymphoma,Journal of Medicinal Chemistry

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Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton’s Tyrosine Kinase for the Treatment of Lymphoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-07 , DOI: 10.1021/acs.jmedchem.2c00324
Jingyu Zhang ₁ , Jinxin Che ₁ , Xiaomin Luo _{2,

3} , Mingfei Wu ₁ , Weijuan Kan ₃ , Yuheng Jin ₁ , Hanlin Wang _{3,

4} , Ao Pang ₁ , Cong Li ₃ , Wenhai Huang ₅ , Shenxin Zeng ₅ , Weihao Zhuang ₁ , Yizhe Wu ₁ , Yongjin Xu ₆ , Yubo Zhou _{2,

3,

7} , Jia Li _{2,

3,

7} , Xiaowu Dong _{1,

8,

9}

Affiliation

Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
School of Pharmacy, Fudan University, Shanghai 200032, China.
Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou 310058, P. R. China.
Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou 310005, P. R. China.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Tsuihang New District, Guangdong 528400, P. R. China.
Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, P. R. China.
Cancer Center, Zhejiang University, Hangzhou 310058, P. R. China.

Bruton’s tyrosine kinase proteolysis-targeting chimeras (BTK-PROTACs) have emerged as a promising approach to address the limitations of BTK inhibitors. However, conducting the rational discovery of orally bioavailable BTK-PROTACs presents significant challenges. In this study, dimensionality reduction analysis and model molecule validation were utilized to identify some key structural features for improving the oral absorption of BTK-PROTACs. The results were applied to optimize the newly discovered BTK-PROTACs B1 and B2. Compound C13 was discovered with improved oral bioavailability, high BTK degradation activity, and selectivity. It exhibited inhibitory effects against different hematologic cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced BTK protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTK-PROTAC for the treatment of lymphoma, and we hope that the strategy will find wide utility.

中文翻译：

发现用于治疗淋巴瘤的布鲁顿酪氨酸激酶的口服生物可利用 PROTAC 的结构特征分析策略

Bruton 的酪氨酸激酶蛋白水解靶向嵌合体 (BTK-PROTACs) 已成为解决 BTK 抑制剂局限性的有希望的方法。然而，进行口服生物可利用的 BTK-PROTAC 的合理发现提出了重大挑战。在这项研究中，降维分析和模型分子验证被用来确定一些关键的结构特征，以改善 BTK-PROTAC 的口服吸收。将结果应用于优化新发现的 BTK-PROTACs B1和B2。化合物C13被发现具有改善的口服生物利用度、高 BTK 降解活性和选择性。它对不同的血液癌细胞表现出抑制作用，并减弱了 BTK 相关的信号通路。口服C13有效降低 BTK 蛋白水平并抑制肿瘤生长。这项研究导致发现了一种用于治疗淋巴瘤的新的口服生物可利用的 BTK-PROTAC，我们希望该策略能够得到广泛的应用。

更新日期：2022-06-07

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