Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas
文献类型：期刊论文
| Author | Song, Pei-ran6; Wan, Zhi-peng4,5; Huang, Ge-ge4,5; Song, Zi-lan3; Zhang, Tao6; Tong, Lin-jiang6; Fang, Yan6; Tang, Hao-tian4,6; Xue, Yu6; Zhan, Zheng-sheng6 |
| Source | ACTA PHARMACOLOGICA SINICA
 |
| Issued Date | 2024-06-04 |
| Pages | 11 |
| Keyword | diffuse large B-cell lymphoma BTK inhibitors drug resistance BTK C481F BTK A428D SYHA1813 |
| ISSN | 1671-4083 |
| DOI | 10.1038/s41401-024-01311-x |
| Corresponding Author | Duan, Wen-hu(whduan@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn) ; Xie, Hua(hxie@simm.ac.cn) |
| English Abstract | Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations. |
| WOS Keyword | B-CELL LYMPHOMA ; TARGETING BTK ; IBRUTINIB ; RECEPTOR |
| Funding Project | High-level Innovative Research Institute, Department of Science and Technology of Guangdong Province[2021B0909050003] ; Zhongshan Municipal Bureau of Science and Technology[2023B2029] ; National Natural Science Foundation of China[82273948] ; Project of Shanghai Institute of Materia Medica, CAS[SIMM0120231001] ; State Key Laboratory of Drug Research[SKLDR-2023-TT-01] ; Institutes for Drug Discovery and Development, CAS[CASIMM0120225003-1] |
| WOS Research Area | Chemistry ; Pharmacology & Pharmacy |
| Language | 英语 |
| WOS ID | WOS:001238570300001 |
| Publisher | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311785]  |
| Collection | 中国科学院上海药物研究所 |
| Corresponding Author | Duan, Wen-hu; Ding, Jian; Zhang, Ao; Xie, Hua |
| Affiliation | 1.Guizhou Med Univ, Sch Pharm, Guiyang 561113, Peoples R China 2.Zunyi Med Univ, Sch Pharm, Zunyi 563006, Peoples R China 3.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharm, Shanghai 200240, Peoples R China 4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 5.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Mol Drug Res Ctr, Div Antitumor Pharmacol & Small, Shanghai 201203, Peoples R China |
| Recommended Citation GB/T 7714 | Song, Pei-ran,Wan, Zhi-peng,Huang, Ge-ge,et al. Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas[J]. ACTA PHARMACOLOGICA SINICA,2024:11. |
| APA | Song, Pei-ran.,Wan, Zhi-peng.,Huang, Ge-ge.,Song, Zi-lan.,Zhang, Tao.,...&Xie, Hua.(2024).Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.ACTA PHARMACOLOGICA SINICA,11. |
| MLA | Song, Pei-ran,et al."Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas".ACTA PHARMACOLOGICA SINICA (2024):11. |
入库方式： OAI收割
来源：上海药物研究所
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