文献类型：期刊文献

英文题名：Mechanistic Insights Into Co-Administration of Allosteric and Orthosteric Drugs to Overcome Drug-Resistance in T315I BCR-ABL1

作者：Zhang, Hao[1,2];Zhu, Mingsheng[3];Li, Mingzi[1];Ni, Duan[4];Wang, Yuanhao[4];Deng, Liping[1];Du, Kui[1];Lu, Shaoyong[4];Shi, Hui[6];Cai, Chen[5]

机构：[1]Shaoxing Univ, Sch Chem & Chem Engn, Shaoxing, Peoples R China;[2]Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Sch Med, Dept Plast & Reconstruct Surg, Shanghai, Peoples R China;[3]Fudan Univ, Dept Anesthesiol, Huashan Hosp, Shanghai, Peoples R China;[4]Shanghai Jiao Tong Univ, Med Chem & Bioinformat Ctr, Sch Med, Shanghai, Peoples R China;[5]Navy Med Univ, Changhai Hosp, Dept VIP Clin, Shanghai, Peoples R China;[6]Navy Med Univ, Changhai Hosp, Dept Resp & Crit Care Med, Shanghai, Peoples R China

年份：2022

卷号：13

外文期刊名：FRONTIERS IN PHARMACOLOGY

收录：SCI-EXPANDED(收录号：WOS:000791378500001)、、Scopus(收录号：2-s2.0-85127951311)、WOS

基金：Funding This research was funded by the Natural Science Foundation of China (No. 22077082).

语种：英文

外文关键词：chronic myelogenous leukemia (CML); BCR-ABL1; tyrosine kinase inhibitors (TKIs); nilotinib; drug resistance; ABL001; allosteric drug; combinatory treatment

外文摘要：Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, driven by the BCR-ABL1 fusion oncoprotein. The discovery of orthosteric BCR-ABL1 tyrosine kinase inhibitors (TKIs) targeting its active ATP-binding pocket, such as first-generation Imatinib and second-generation Nilotinib (NIL), has profoundly revolutionized the therapeutic landscape of CML. However, currently targeted therapeutics still face considerable challenges with the inevitable emergence of drug-resistant mutations within BCR-ABL1. One of the most common resistant mutations in BCR-ABL1 is the T315I gatekeeper mutation, which confers resistance to most current TKIs in use. To resolve such conundrum, co-administration of orthosteric TKIs and allosteric drugs offers a novel paradigm to tackle drug resistance. Remarkably, previous studies have confirmed that the dual targeting BCR-ABL1 utilizing orthosteric TKI NIL and allosteric inhibitor ABL001 resulted in eradication of the CML xenograft tumors, exhibiting promising therapeutic potential. Previous studies have demonstrated the cooperated mechanism of two drugs. However, the conformational landscapes of synergistic effects remain unclear, hampering future efforts in optimizations and improvements. Hence, extensive large-scale molecular dynamics (MD) simulations of wide type (WT), WT-NIL, T315I, T315I-NIL, T315I-ABL001 and T315I-ABL001-NIL systems were carried out in an attempt to address such question. Simulation data revealed that the dynamic landscape of NIL-bound BCR-ABL1 was significantly reshaped upon ABL001 binding, as it shifted from an active conformation towards an inactive conformation. The community network of allosteric signaling was analyzed to elucidate the atomistic overview of allosteric regulation within BCR-ABL1. Moreover, binding free energy analysis unveiled that the affinity of NIL to BCR-ABL1 increased by the induction of ABL001, which led to its favorable binding and the release of drug resistance. The findings uncovered the in-depth structural mechanisms underpinning dual-targeting towards T315I BCR-ABL1 to overcome its drug resistance and will offer guidance for the rational design of next generations of BCR-ABL1 modulators and future combinatory therapeutic regimens.