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

作　　者：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 Xi 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2024年第10期2163-2173,共11页中国药理学报（英文版）

基　　金：supported by High-level Innovative Research Institute,Department of Science and Technology of Guangdong Province(2021B0909050003);Zhongshan Municipal Bureau of Science and Technology(2023B2029);the National Natural Science Foundation of China(82273948);the 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 and-2).

摘　　要：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 IC_(50) value of 0.5 nM,comparable to a commercially available BTK inhibitor ibrutinib(IC_(50)=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.

关 键 词：diffuse large B-cell lymphoma BTK inhibitors drug resistance BTK C481F BTK A428D SYHA1813 

分 类 号：R733[医药卫生—肿瘤]