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Title: Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics

Journal Article · · PLoS ONE
 [1];  [2];  [1];  [2];  [1];  [2]
  1. Seattle Genetics, Inc., Bothell, WA (United States)
  2. Paul Scherrer Institute (PSI), Villigen (Switzerland)

The auristatin class of microtubule destabilizers are highly potent cytotoxic agents against several cancer cell types when delivered as antibody drug conjugates. Here we describe the high resolution structures of tubulin in complex with both monomethyl auristatin E and F and unambiguously define the trans-configuration of both ligands at the Val-Dil amide bond in their tubulin bound state. Moreover, we illustrate how peptidic vinca-site agents carrying terminal carboxylate residues may exploit an observed extended hydrogen bond network with the M-loop Arg278 to greatly improve the affinity of the corresponding analogs and to maintain the M-loop in an incompatible conformation for productive lateral tubulin-tubulin contacts in microtubules. Our results highlight a potential, previously undescribed molecular mechanism by which peptidic vinca-site agents maintain unparalleled potency as microtubule-destabilizing agents.

Research Organization:
Seattle Genetics, Inc., Bothell, WA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Swiss National Science Foundation (SNSF); Seattle Genetics Inc
Grant/Contract Number:
AC02-05CH11231; 310030B_138659
OSTI ID:
1337464
Alternate ID(s):
OSTI ID: 1903867
Journal Information:
PLoS ONE, Vol. 11, Issue 8; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 101 works
Citation information provided by
Web of Science

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Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma journal September 2019
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Comparison of a mouse and a novel human scFv-SNAP-auristatin F drug conjugate with potent activity against EGFR-overexpressing human solid tumor cells text January 2017
Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours? journal March 2018
Advances and Limitations of Antibody Drug Conjugates for Cancer journal July 2021
Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma journal December 2019