DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody-Drug Conjugate Modality.

Autor:	Sivaprakasam P; Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States., McDonald I; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Iwuagwu C; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Chowdari NS; Discovery Chemistry, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Peese KM; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Langley DR; Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Cheng H; Discovery Chemistry, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Luzung MR; Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States., Schmidt MA; Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States., Zheng B; Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States., Tan Y; Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States., Cho P; Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States., Rakshit S; Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India., Lakshminarasimhan T; Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India., Guturi S; Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India., Kanagavel K; Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India., Kanusu U; Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India., Niyogi AG; Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India., Sidhar S; Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India., Vaidyanathan R; Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India., Eastgate MD; Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States., Kotapati S; Discovery Biotherapeutics, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Deshpande M; Discovery Biotherapeutics, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Pan C; Cell Biology and Pharmacology, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Cardarelli PM; Cell Biology and Pharmacology, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Xie C; Lead Discovery and Optimization, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, United States., Rao C; Discovery Biotherapeutics, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Holder P; Discovery Biotherapeutics, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Sarma G; Discovery Biotherapeutics, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States., Vite G; Discovery Chemistry, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, United States., Gangwar S; Discovery Chemistry, Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Feb 10; Vol. 12 (3), pp. 404-412. Date of Electronic Publication: 2021 Feb 10 (Print Publication: 2021).
DOI:	10.1021/acsmedchemlett.0c00578
Abstrakt:	A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1 H -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. Competing Interests: The authors declare no competing financial interest. (© 2021 American Chemical Society.)
Databáze:	MEDLINE
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