1185019-82-2Relevant articles and documents
DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody-Drug Conjugate Modality
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
, p. 404 - 412 (2021)
A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-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 in vitro 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) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.
Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
Boy, Kenneth M.,Guernon, Jason M.,Zuev, Dmitry S.,Xu, Li,Zhang, Yunhui,Shi, Jianliang,Marcin, Lawrence R.,Higgins, Mendi A.,Wu, Yong-Jin,Krishnananthan, Subramaniam,Li, Jianqing,Trehan, Ashok,Smith, Daniel,Toyn, Jeremy H.,Meredith, Jere E.,Burton, Catherine R.,Kimura, S. Roy,Zvyaga, Tatyana,Zhuo, Xiaoliang,Lentz, Kimberley A.,Grace, James E.,Denton, Rex,Morrison, John S.,Mathur, Arvind,Albright, Charles F.,Ahlijanian, Michael K.,Olson, Richard E.,Thompson, Lorin A.,Macor, John E.
supporting information, p. 312 - 317 (2019/03/08)
A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβsub
FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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Paragraph 1023, (2017/05/14)
The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.