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.
摘要：
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BTK抑制剂的功效证实了这一点。然而,有助于避免BTK抑制的靶向BTK突变导致限制BTK抑制剂疗效的耐药性。在这项研究中，我们采用了基于已建立的BTK抑制剂的基于结构的药物设计策略，并产生了一系列BTK靶向化合物。其中,具有独特三环结构的化合物S-016表现出有效的BTK激酶抑制活性，IC50值为0.5nM，与市售BTK抑制剂依鲁替尼（IC50=0.4nM）相当。S-016作为一种新型的不可逆BTK抑制剂，与依鲁替尼相比，显示出更高的激酶选择性，并且在体外和体内对B细胞淋巴瘤具有显着的治疗效果。此外，我们产生了携带BTKC481F或A428D的BTK抑制剂耐药淋巴瘤细胞,以探索克服耐药的策略.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，已知支持肿瘤进展的过程。有趣的是，我们证明了SYHA1813，一种靶向VEGFR和CSF1R的化合物，在BTK突变和野生型BTKDLBCL模型中,通过抑制血管生成和调节巨噬细胞极化,有效重塑了肿瘤微环境(TME),并显著克服了对BTK抑制剂的获得性耐药性.总的来说,这项研究不仅促进了新的BTK抑制剂的开发，而且为B细胞淋巴瘤提供了创新的治疗策略，包括具有BTK突变的那些。
