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Characterisation of the carboxypeptidase G2 catalytic site and design of new inhibitors for cancer therapy

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Jeyaharan, Dhadchayini, Brackstone, Carla, Schouten, James, Davis, Paul and Dixon, Ann M. (2018) Characterisation of the carboxypeptidase G2 catalytic site and design of new inhibitors for cancer therapy. ChemBioChem, 19 (18). pp. 1959-1968. doi:10.1002/cbic.201800186

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Official URL: https://doi.org/10.1002/cbic.201800186

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Abstract

The enzyme carboxypeptidase G2 (CPG2) is used in antibody‐directed enzyme prodrug therapy (ADEPT) to catalyse the formation of an active drug from an inert prodrug. Free CPG2 in the bloodstream must be inhibited before administration of the prodrug in order to avoid a systemic reaction in the patient. Although a few small‐molecule CPG2 inhibitors have been reported, none has been taken forward thus far. This lack of progress is due in part to a lack of structural understanding of the CPG2 active site as well as the absence of small molecules that can block the active site whilst targeting the complex for clearance. The work described here aimed to address both areas. We report the structural/functional impact of extensive point mutation across the putative CPG2 catalytic site and adjacent regions for the first time, revealing that residues outside the catalytic region (K208A, S210A and T357A) are crucial to enzyme activity. We also describe novel molecules that inhibit CPG2 whilst maintaining the accessibility of galactosylated moieties aimed at targeting the enzyme for clearance. This work acts as a platform for the future development of high‐affinity CPG2 inhibitors that occupy new chemical space and will advance the safe application of ADEPT in cancer treatment.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science > Chemistry
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Carboxypeptidases, Prodrugs
Journal or Publication Title: ChemBioChem
Publisher: Wiley
ISSN: 1439-4227
Official Date: 17 September 2018
Dates:
DateEvent
17 September 2018Published
3 July 2018Available
22 June 2018Accepted
Date of first compliant deposit: 1 November 2018
Volume: 19
Number: 18
Page Range: pp. 1959-1968
DOI: 10.1002/cbic.201800186
Status: Peer Reviewed
Publication Status: Published
Publisher Statement: "This is the peer reviewed version of the following article:D. Jeyaharan, C. Brackstone, J. Schouten, P. Davis, A. M. Dixon, ChemBioChem 2018, 19, 1959. which has been published in final form at https://doi.org/10.1002/cbic.201800186 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions."
Access rights to Published version: Restricted or Subscription Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
BB/I015965/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
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