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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
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 | ||||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology |
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| 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: |
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| 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: |
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