Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity

Helen M. Sheldrake; Sandra Travica; Inger Johansson; Paul M. Loadman; Mark Sutherland; Lina Elsalem; Nicola Illingworth; Alexander J. Cresswell; Tristan Reuillon; Steven D. Shnyder; Souren Mkrtchian; Mark Searcey; Magnus Ingelman-Sundberg; Laurence H. Patterson; Klaus Pors

doi:10.1021/jm4000209

Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity

Helen M. Sheldrake, Sandra Travica, Inger Johansson, Paul M. Loadman, Mark Sutherland, Lina Elsalem, Nicola Illingworth, Alexander J. Cresswell, Tristan Reuillon, Steven D. Shnyder, Souren Mkrtchian, Mark Searcey, Magnus Ingelman-Sundberg, Laurence H. Patterson, Klaus Pors

Department of Chemistry

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37 Citations (SciVal)

Abstract

A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM-nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors.

Original language	English
Pages (from-to)	6273-6277
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	15
DOIs	https://doi.org/10.1021/jm4000209
Publication status	Published - 8 Aug 2013

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Sheldrake, H. M., Travica, S., Johansson, I., Loadman, P. M., Sutherland, M., Elsalem, L., Illingworth, N., Cresswell, A. J., Reuillon, T., Shnyder, S. D., Mkrtchian, S., Searcey, M., Ingelman-Sundberg, M., Patterson, L. H., & Pors, K. (2013). Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity. Journal of Medicinal Chemistry, 56(15), 6273-6277. https://doi.org/10.1021/jm4000209

Sheldrake, HM, Travica, S, Johansson, I, Loadman, PM, Sutherland, M, Elsalem, L, Illingworth, N, Cresswell, AJ, Reuillon, T, Shnyder, SD, Mkrtchian, S, Searcey, M, Ingelman-Sundberg, M, Patterson, LH & Pors, K 2013, 'Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity', Journal of Medicinal Chemistry, vol. 56, no. 15, pp. 6273-6277. https://doi.org/10.1021/jm4000209

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abstract = "A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM-nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors. ",

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doi = "10.1021/jm4000209",

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AU - Sheldrake, Helen M.

AU - Travica, Sandra

AU - Johansson, Inger

AU - Loadman, Paul M.

AU - Sutherland, Mark

AU - Elsalem, Lina

AU - Illingworth, Nicola

AU - Cresswell, Alexander J.

AU - Reuillon, Tristan

AU - Shnyder, Steven D.

AU - Mkrtchian, Souren

AU - Searcey, Mark

AU - Ingelman-Sundberg, Magnus

AU - Patterson, Laurence H.

AU - Pors, Klaus

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AB - A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM-nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors.

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Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity

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