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Publication Abstract from PubMed

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 alpha/beta 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.

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.,Nicolaou KC, Pan S, Pulukuri KK, Ye Q, Rigol S, Erande RD, Vourloumis D, Nocek BP, Munneke S, Lyssikatos J, Valdiosera A, Gu C, Lin B, Sarvaiaya H, Trinidad J, Sandoval J, Lee C, Hammond M, Aujay M, Taylor N, Pysz M, Purcell JW, Gavrilyuk J J Org Chem. 2021 Feb 19;86(4):3377-3421. doi: 10.1021/acs.joc.0c02755. Epub 2021 , Feb 5. PMID:33544599^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.