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

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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.

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 - 11 Jul 2013

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10.1021/jm4000209

Cite this

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

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

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.",

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

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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

TY - JOUR

T1 - Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity

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

PY - 2013/7/11

Y1 - 2013/7/11

N2 - 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.

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.

U2 - 10.1021/jm4000209

DO - 10.1021/jm4000209

M3 - Article

VL - 56

SP - 6273

EP - 6277

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 15

ER -