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
posted on 2021-02-05, 18:33authored byK. C. Nicolaou, Saiyong Pan, Kiran K. Pulukuri, Qiuji Ye, Stephan Rigol, Rohan D. Erande, Dionisios Vourloumis, Bogusław
P. Nocek, Stefan Munneke, Joseph Lyssikatos, Amanda Valdiosera, Christine Gu, Baiwei Lin, Hetal Sarvaiaya, Jose Trinidad, Joseph Sandoval, Christina Lee, Mikhail Hammond, Monette Aujay, Nicole Taylor, Marybeth Pysz, James W. Purcell, Julia Gavrilyuk
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.