中国科学院上海药物研究所Hua Xie等人近期取得重要工作进展。他们开发了新型BTK抑制剂S-016并确定治疗淋巴瘤（包括对BTK抑制剂耐药的淋巴瘤）的新策略。相关研究成果2024年6月4日在线发表于《中国药理学报》杂志上。

据介绍，布鲁顿酪氨酸激酶（BTK）已成为B细胞恶性肿瘤的治疗靶点，各种不可逆或可逆的BTK抑制剂的疗效证实了这一点。然而，促进逃避BTK抑制的靶向BTK突变会导致耐药性，从而限制BTK抑制剂的治疗效果。

研究人员采用了基于结构的药物设计策略，基于已建立的BTK抑制剂，获得了一系列BTK靶向化合物。其中，具有独特三环结构的化合物S-016表现出强大的BTK激酶抑制活性，IC₅₀值为0.5nM，与市售的BTK抑制剂伊布替尼（ibrutinib）（IC₅₀＝0.4nM）相当。S-016作为一种新型的不可逆BTK抑制剂，与伊布替尼相比，在体外和体内均表现出优越的激酶选择性和对B细胞淋巴瘤的显著治疗效果。

此外，研究人员开发了携带BTK C481F或A428D的BTK抑制剂抗性淋巴瘤细胞，以探索克服耐药性的策略。这些DLBCL细胞与M0巨噬细胞的共培养导致M0巨噬细胞向M2表型极化，这一过程已知支持肿瘤进展。研究人员证明SYHA1813（一种靶向VEGFR和CSF1R的化合物）通过抑制血管生成和调节巨噬细胞极化，能有效重塑肿瘤微环境（TME），并克服BTK突变和野生型BTK-DLBCL模型中对BTK抑制剂的获得性耐药性。

总之，这项研究不仅促进了新的BTK抑制剂的开发，而且为B细胞淋巴瘤（包括BTK突变的淋巴瘤）提供了创新的治疗策略。

附：英文原文

Title: Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas

Author: Song, Pei-ran, Wan, Zhi-peng, Huang, Ge-ge, Song, Zi-lan, Zhang, Tao, Tong, Lin-jiang, Fang, Yan, Tang, Hao-tian, Xue, Yu, Zhan, Zheng-sheng, Feng, Fang, Li, Yan, Shi, Wen-hao, Huang, Yu-qing, Chen, Yi, Duan, Wen-hu, Ding, Jian, Zhang, Ao, Xie, Hua

Issue&Volume: 2024-06-04

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.

DOI: 10.1038/s41401-024-01311-x

Source: https://www.nature.com/articles/s41401-024-01311-x