2. Academic Validation
  3. Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas

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 Pharmacol Sin. 2024 Jun 4. doi: 10.1038/s41401-024-01311-x.
Pei-Ran Song # 1,  Zhi-Peng Wan # 2 3,  Ge-Ge Huang # 2 3,  Zi-Lan Song # 4,  Tao Zhang 1,  Lin-Jiang Tong 1,  Yan Fang 1,  Hao-Tian Tang 1 3,  Yu Xue 1,  Zheng-Sheng Zhan 1,  Fang Feng 1,  Yan Li 1,  Wen-Hao Shi 3 5,  Yu-Qing Huang 3 6,  Yi Chen 1,  Wen-Hu Duan 7,  Jian Ding 8,  Ao Zhang 9,  Hua Xie 10 11 12
Affiliations

Affiliations

  • 1 Division of Antitumor Pharmacology & Small-Molecule Drug Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
  • 4 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 5 School of Pharmacy, Zunyi Medical University, Zunyi, 563006, China.
  • 6 School of Pharmacy, Guizhou Medical University, Guiyang, 561113, China.
  • 7 Division of Antitumor Pharmacology & Small-Molecule Drug Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. whduan@simm.ac.cn.
  • 8 Division of Antitumor Pharmacology & Small-Molecule Drug Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jding@simm.ac.cn.
  • 9 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. ao6919zhang@sjtu.edu.cn.
  • 10 Division of Antitumor Pharmacology & Small-Molecule Drug Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. hxie@simm.ac.cn.
  • 11 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. hxie@simm.ac.cn.
  • 12 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. hxie@simm.ac.cn.
  • # Contributed equally.
PMID: 38834683 DOI: 10.1038/s41401-024-01311-x
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.

Keywords

BTK A428D; BTK C481F; BTK inhibitors; SYHA1813; diffuse large B-cell lymphoma; drug resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-158064
    BTK抑制剂
    Btk
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