基于DNA模型的某些用于抗体-药物偶联物形式的稠合苯二氮䓬杂合payloads的设计与执行
DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody-Drug Conjugate Modality.
作者信息
Sivaprakasam Prasanna, McDonald Ivar, Iwuagwu Christiana, Chowdari Naidu S, Peese Kevin M, Langley David R, Cheng Heng, Luzung Michael R, Schmidt Michael A, Zheng Bin, Tan Yichen, Cho Patricia, Rakshit Souvik, Lakshminarasimhan Thirumalai, Guturi Sivakrishna, Kanagavel Kishorekumar, Kanusu Umamaheswararao, Niyogi Ankita G, Sidhar Somprabha, Vaidyanathan Rajappa, Eastgate Martin D, Kotapati Srikanth, Deshpande Madhura, Pan Chin, Cardarelli Pina M, Xie Chunshan, Rao Chetana, Holder Patrick, Sarma Ganapathy, Vite Gregory, Gangwar Sanjeev
机构信息
Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
出版信息
ACS Med Chem Lett. 2021 Feb 10;12(3):404-412. doi: 10.1021/acsmedchemlett.0c00578. eCollection 2021 Mar 11.
A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1-pyrrol-3-yl)benzene ("MPB") payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the "MPB" binding component and guided structure-activity relationship generation. This hybrid series of payloads exhibited excellent activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody-drug conjugate (ADC) demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.
设计并实施了一个新系列，该系列具有与四氢异喹啉稠合苯并二氮杂䓬（TBD）环系统相结合的（1-甲基-1-吡咯-3-基）苯（“MPB”）有效载荷类似物，用于与单克隆抗体偶联以进行抗癌治疗。DNA模型有助于合理确定“MPB”结合成分的修饰，并指导构效关系的建立。当针对一系列不同的癌细胞系进行测试时，这种混合系列的有效载荷表现出优异的活性。其中一种有效载荷附加了可被溶酶体裂解的肽接头，并通过由细菌转谷氨酰胺酶（BTGase）介导的位点特异性偶联方法与抗间皮素抗体偶联。抗体药物偶联物（ADC）表现出良好的血浆稳定性和溶酶体裂解能力。单次静脉注射剂量的ADC（5或10 nmol/kg）在N87胃癌异种移植模型中显示出强大的疗效。
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