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Design, synthesis, and biological evaluation of tubulysin analogues, linker-drugs, and antibody–drug conjugates, insights into structure–activity relationships, and tubulysin–tubulin binding derived from X-ray crystallographic analysis

DOI: 10.1021/acs.joc.0c02755 DOI Help

Authors: Kyriacos C. Nicolaou (Rice University) , Saiyong Pan (Rice University) , Kiran K. Pulukuri (Rice University) , Qiuji Ye (Rice University) , Stephan Rigol (Rice University) , Rohan D. Erande (Rice University) , Dionisios Vourloumis (Rice University; National Centre for Scientific Research “Demokritos”) , Bogusław P. Nocek (AbbVie Inc) , Stefan Munneke (AbbVie Inc) , Joseph Lyssikatos (AbbVie Inc) , Amanda Valdiosera (AbbVie Inc) , Christine Gu (AbbVie Inc) , Baiwei Lin (AbbVie Inc) , Hetal Sarvaiaya (AbbVie Inc) , Jose Trinidad (AbbVie Inc) , Joseph Sandoval (AbbVie Inc) , Christina Lee (AbbVie Inc) , Mikhail Hammond (AbbVie Inc) , Monette Aujay (AbbVie Inc) , Nicole Taylor (AbbVie Inc) , Marybeth Pysz (AbbVie Inc) , James W. Purcell (AbbVie Inc) , Julia Gavrilyuk (AbbVie Inc)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: The Journal Of Organic Chemistry

State: Published (Approved)
Published: February 2021

Abstract: Molecular design, synthesis, and biological evaluation of tubulysin analogues, linker-drugs, and antibody–drug conjugates are described. Among the new discoveries reported is the identification of new potent analogues within the tubulysin family that carry a C11 alkyl ether substituent, rather than the usual ester structural motif at that position, a fact that endows the former with higher plasma stability than that of the latter. Also described herein are X-ray crystallographic analysis studies of two tubulin–tubulysin complexes formed within the α/β interface between two tubulin heterodimers and two highly potent tubulysin analogues, one of which exhibited a different binding mode to the one previously reported for tubulysin M. The X-ray crystallographic analysis-derived new insights into the binding modes of these tubulysin analogues explain their potencies and provide inspiration for further design, synthesis, and biological investigations within this class of antitumor agents. A number of these analogues were conjugated as payloads with appropriate linkers at different sites allowing their attachment onto targeting antibodies for cancer therapies. A number of such antibody–drug conjugates were constructed and tested, both in vivo and in vitro, leading to the identification of at least one promising ADC (Herceptin–LD3), warranting further investigations.

Journal Keywords: Organic acids; Ethers; Organic compounds; Alkyls; Amines

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Documents:
acs.joc.0c02755.pdf

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