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

in Acta pharmacologica Sinica by Pei-Ran Song, Zhi-Peng Wan, Ge-Ge Huang, Zi-Lan Song, Tao Zhang, Lin-Jiang Tong, Yan Fang, Hao-Tian Tang, Yu Xue, Zheng-Sheng Zhan, Fang Feng, Yan Li, Wen-Hao Shi, Yu-Qing Huang, Yi Chen, Wen-Hu Duan, Jian Ding, Ao Zhang, Hua Xie

TLDR

  • The study aimed to develop new drugs to treat a type of cancer called B-cell lymphoma. The researchers used a special type of drug called a BTK inhibitor to treat the cancer. However, some types of cancer cells can become resistant to the drug, which limits its effectiveness. The researchers used a special type of drug called S-016, which was designed to target the cancer cells that were resistant to the BTK inhibitor. The researchers also found a way to change the environment around the cancer cells to make them more vulnerable to the drug. The key takeaway is that S-016 and other drugs like it could be used to treat B-cell lymphoma, and that strategies for overcoming resistance to BTK inhibitors could be explored in future research.

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 ICvalue of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC= 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.

Overview

  • The study aimed to develop new BTK inhibitors for B-cell malignancies and explore strategies for overcoming resistance to BTK inhibitors. The methodology involved structure-based drug design strategies based on established BTK inhibitors, and the results showed that compound S-016 exhibited potent BTK kinase inhibitory activity and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. The study also generated BTK inhibitor-resistant lymphoma cells and demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment and overcame resistance to BTK inhibitors. The primary objective of the study was to develop new BTK inhibitors and explore strategies for overcoming resistance to BTK inhibitors in B-cell lymphomas. The study's findings suggest that S-016 and SYHA1813 could be potential therapeutic options for B-cell lymphomas, including those with BTK mutations.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions, including the efficacy of various BTK inhibitors and the effects of BTK inhibitor-resistant lymphoma cells on the tumor microenvironment. The results showed that compound S-016 exhibited potent BTK kinase inhibitory activity and significant therapeutic effects against B-cell lymphoma, while SYHA1813 effectively reshaped the tumor microenvironment and overcame resistance to BTK inhibitors. The study identified that BTK C481F or A428D mutations facilitated evasion from BTK inhibition and led to resistance, which limited the therapeutic efficacy of BTK inhibitors. The key findings of the study suggest that S-016 and SYHA1813 could be potential therapeutic options for B-cell lymphomas, including those with BTK mutations, and that strategies for overcoming resistance to BTK inhibitors, such as targeting the tumor microenvironment, could be explored in future research.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest that S-016 and SYHA1813 could be potential therapeutic options for B-cell lymphomas, including those with BTK mutations. The study also identified that strategies for overcoming resistance to BTK inhibitors, such as targeting the tumor microenvironment, could be explored in future research. The limitations of the study include the need for further preclinical and clinical studies to evaluate the safety and efficacy of S-016 and SYHA1813 in humans. Future research directions could include the development of combination therapies that target multiple pathways involved in B-cell lymphoma progression, as well as the exploration of novel approaches for overcoming resistance to BTK inhibitors, such as immunotherapy or gene therapy.
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