机构：[1]The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University[2]Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, China.[2]Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.[3]Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.四川大学华西医院[4]Department of Biological Medicines &[6]Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China.[5]Drug Research and Bioinformatics Group, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.[6]Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Singapore, Singapore.[10]Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, 518055, China
Cancers resist targeted therapeutics by drug-escape signaling. Multitarget drugs co-targeting cancer and drug-escape mediators (DEMs) are clinically advantageous. DEM coverage may be expanded by drug combinations. This work evaluated to what extent the kinase DEMs (KDEMs) can be optimally co-targeted by drug combinations based on target promiscuities of individual drugs. We focused on 41 approved and 28 clinical trial small molecule kinase inhibitor drugs with available experimental kinome and clinical pharmacokinetic data. From the kinome inhibitory profiles of these drugs, drug combinations were assembled for optimally co-targeting an established cancer target (EGFR, HER2, ABL1, or MEK1) and 9-16 target-associated KDEMs at comparable potency levels as that against the cancer target. Each set of two-, three-, and four-drug combinations co-target 36-71%, 44-89%, 50-88%, and 27-55% KDEMs of EGFR, HER2, ABL1, and MEK1, respectively, compared with the 36, 33, 38, and 18% KDEMs maximally co-targeted by an existing drug or drug combination approved or clinically tested for the respective cancer. Some co-targeted KDEMs are not covered by any existing drug or drug combination. Our work suggested that novel drug combinations may be constructed for optimally co-targeting cancer and drug escape by the exploitation of drug target promiscuities.
基金：
National Key R&D Program of China, Synthetic Biology Research, Grant/Award Number:2019YFA0905900; National Natural Science Foundation of China, Grant/Award Numbers:81973512, 91856126; Shenzhen Science,Technology and Innovation Commission grants, Grant/Award Number:JCYJ20170413113448742,2017B030314083,JCYJ20170816170342439; Shenzhen Bay Laboratory, Grant/Award Number: 201901;Shenzhen Development and Reform Committee, Grant/Award Numbers: 2019156,20151961; Singapore Academic Funds, Grant/Award Number: R-148-000-273-114
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|3 区医学
小类|3 区药物化学3 区药学
最新[2023]版：
大类|4 区医学
小类|3 区药物化学4 区药学
第一作者：
第一作者机构：[1]The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University[2]Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen, China.[2]Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
通讯作者：
通讯机构：[1]The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University[6]Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China.[6]Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Singapore, Singapore.[*1]The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University[*2]Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543, Singapore
推荐引用方式(GB/T 7714)：
Shangying Chen,Sheng Yong Yang,Xian Zeng,et al.Combining kinase inhibitors for optimally co-targeting cancer and drug escape by exploitation of drug target promiscuities.[J].Drug development research.2021,82(1):133-142.doi:10.1002/ddr.21738.
APA：
Shangying Chen,Sheng Yong Yang,Xian Zeng,Feng Zhu,Ying Tan...&Yu Zong Chen.(2021).Combining kinase inhibitors for optimally co-targeting cancer and drug escape by exploitation of drug target promiscuities..Drug development research,82,(1)
MLA：
Shangying Chen,et al."Combining kinase inhibitors for optimally co-targeting cancer and drug escape by exploitation of drug target promiscuities.".Drug development research 82..1(2021):133-142
