Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 6317-6329 |
| Number of pages | 13 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 56 |
| Issue number | 16 |
| Early online date | 22 Jul 2013 |
| DOIs | |
| Publication status | Published - 22 Aug 2013 |
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Keywords
- drug resistance
- cancer chemotherapy
- chemotherapeutic failure
- molecular mechanism of resistance
- mitotic kinesin Eg5
- second-generation ispinesib analogue SB743921
- phase I/II clinical candidate
- allosteric resistance mechanism
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The mitotic kinesin Eg5 overcomes inhibition to the phase I/II clinical candidate SB743921 by an allosteric resistance mechanism. / Talapatra, Sandeep K.; Anthony, Nahoum Guillaume Hsuan; MacKay, Simon; Kozielski, Frank.
In: Journal of Medicinal Chemistry, Vol. 56, No. 16, 22.08.2013, p. 6317-6329.Research output: Contribution to journal › Article
TY - JOUR
T1 - The mitotic kinesin Eg5 overcomes inhibition to the phase I/II clinical candidate SB743921 by an allosteric resistance mechanism
AU - Talapatra, Sandeep K.
AU - Anthony, Nahoum Guillaume Hsuan
AU - MacKay, Simon
AU - Kozielski, Frank
PY - 2013/8/22
Y1 - 2013/8/22
N2 - Development of drug resistance during cancer chemotherapy is one of the major causes of chemotherapeutic failure for the majority of clinical agents. The aim of this study was to investigate the underlying molecular mechanism of resistance developed by the mitotic kinesin Eg5 against the potent second-generation ispinesib analogue SB743921 (1), a phase I/II clinical candidate. Biochemical and biophysical data demonstrate that point mutations in the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold. Surprisingly, the structures of wild type and mutant Eg5 in complex with 1 display no apparent structural changes in the binding configuration of the drug candidate. Furthermore, ITC and modelling approaches reveal that resistance to 1 is not through conventional steric effects at the binding site, but through reduced flexibility and changes in energy fluctuation pathways through the protein that influence its function. This is a phenomenon we have called 'resistance by allostery'.
AB - Development of drug resistance during cancer chemotherapy is one of the major causes of chemotherapeutic failure for the majority of clinical agents. The aim of this study was to investigate the underlying molecular mechanism of resistance developed by the mitotic kinesin Eg5 against the potent second-generation ispinesib analogue SB743921 (1), a phase I/II clinical candidate. Biochemical and biophysical data demonstrate that point mutations in the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold. Surprisingly, the structures of wild type and mutant Eg5 in complex with 1 display no apparent structural changes in the binding configuration of the drug candidate. Furthermore, ITC and modelling approaches reveal that resistance to 1 is not through conventional steric effects at the binding site, but through reduced flexibility and changes in energy fluctuation pathways through the protein that influence its function. This is a phenomenon we have called 'resistance by allostery'.
KW - drug resistance
KW - cancer chemotherapy
KW - chemotherapeutic failure
KW - molecular mechanism of resistance
KW - mitotic kinesin Eg5
KW - second-generation ispinesib analogue SB743921
KW - phase I/II clinical candidate
KW - allosteric resistance mechanism
UR - http://pubs.acs.org/journal/jmcmar
U2 - 10.1021/jm4006274
DO - 10.1021/jm4006274
M3 - Article
VL - 56
SP - 6317
EP - 6329
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 16
ER -