Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

Stephen Brand; Laura A. T. Cleghorn; Stuart P. McElroy; David A. Robinson; Victoria C. Smith; Irene Hallyburton; Justin R. Harrison; Neil R. Norcross; Daniel Spinks; Tracy Bayliss; Suzanne Norval; Laste Stojanovski; Leah S. Torrie; Julie A. Frearson; Ruth Brenk; Alan H. Fairlamb; Michael A. J. Ferguson; Kevin D. Read; Paul G. Wyatt; Ian H. Gilbert

doi:10.1021/jm201091t

Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

Stephen Brand, Laura A. T. Cleghorn, Stuart P. McElroy, David A. Robinson, Victoria C. Smith, Irene Hallyburton, Justin R. Harrison, Neil R. Norcross, Daniel Spinks, Tracy Bayliss, Suzanne Norval, Laste Stojanovski, Leah S. Torrie, Julie A. Frearson, Ruth Brenk, Alan H. Fairlamb, Michael A. J. Ferguson, Kevin D. Read, Paul G. Wyatt, Ian H. Gilbert (Lead / Corresponding author)

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Abstract

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

Original language	English
Pages (from-to)	140-152
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	1
DOIs	https://doi.org/10.1021/jm201091t
Publication status	Published - 12 Jan 2012

Keywords

CANDIDA-ALBICANS
TRYPANOSOMA-BRUCEI
DRUG DISCOVERY
PEPTIDOMIMETIC INHIBITORS
SELECTIVE INHIBITORS
DIPEPTIDE AMIDES
PROTEIN
DESIGN
POTENT
BENZOFURANS

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10.1021/jm201091t

Publisher's final version
Reprinted with permission from Brand, S, Cleghorn, LAT, McElroy, SP, Robinson, DA, Smith, VC, Hallyburton, I, Harrison, JR, Norcross, NR, Spinks, D, Bayliss, T, Norval, S, Stojanovski, L, Torrie, LS, Frearson, JA, Brenk, R, Fairlamb, AH, Ferguson, MAJ, Read, KD, Wyatt, PG & Gilbert, IH 2012, 'Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors' Journal of Medicinal Chemistry, vol 55, no. 1, pp. 140-152.. Copyright 2012 American Chemical Society.
Final published version, 4.78 MB

http://ukpmc.ac.uk/articles/PMC3256935

Cite this

Brand, S., Cleghorn, L. A. T., McElroy, S. P., Robinson, D. A., Smith, V. C., Hallyburton, I., Harrison, J. R., Norcross, N. R., Spinks, D., Bayliss, T., Norval, S., Stojanovski, L., Torrie, L. S., Frearson, J. A., Brenk, R., Fairlamb, A. H., Ferguson, M. A. J., Read, K. D., Wyatt, P. G., & Gilbert, I. H. (2012). Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors. Journal of Medicinal Chemistry, 55(1), 140-152. https://doi.org/10.1021/jm201091t

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abstract = "N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.",

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author = "Stephen Brand and Cleghorn, {Laura A. T.} and McElroy, {Stuart P.} and Robinson, {David A.} and Smith, {Victoria C.} and Irene Hallyburton and Harrison, {Justin R.} and Norcross, {Neil R.} and Daniel Spinks and Tracy Bayliss and Suzanne Norval and Laste Stojanovski and Torrie, {Leah S.} and Frearson, {Julie A.} and Ruth Brenk and Fairlamb, {Alan H.} and Ferguson, {Michael A. J.} and Read, {Kevin D.} and Wyatt, {Paul G.} and Gilbert, {Ian H.}",

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Brand, S, Cleghorn, LAT, McElroy, SP, Robinson, DA, Smith, VC, Hallyburton, I , Harrison, JR, Norcross, NR, Spinks, D, Bayliss, T , Norval, S , Stojanovski, L , Torrie, LS, Frearson, JA, Brenk, R, Fairlamb, AH , Ferguson, MAJ , Read, KD, Wyatt, PG & Gilbert, IH 2012, 'Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors', Journal of Medicinal Chemistry, vol. 55, no. 1, pp. 140-152. https://doi.org/10.1021/jm201091t

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AU - McElroy, Stuart P.

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AU - Smith, Victoria C.

AU - Hallyburton, Irene

AU - Harrison, Justin R.

AU - Norcross, Neil R.

AU - Spinks, Daniel

AU - Bayliss, Tracy

AU - Norval, Suzanne

AU - Stojanovski, Laste

AU - Torrie, Leah S.

AU - Frearson, Julie A.

AU - Brenk, Ruth

AU - Fairlamb, Alan H.

AU - Ferguson, Michael A. J.

AU - Read, Kevin D.

AU - Wyatt, Paul G.

AU - Gilbert, Ian H.

PY - 2012/1/12

Y1 - 2012/1/12

N2 - N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

AB - N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC50 = 2 nM) and T. brucei (EC50 = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

KW - CANDIDA-ALBICANS

KW - TRYPANOSOMA-BRUCEI

KW - DRUG DISCOVERY

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KW - SELECTIVE INHIBITORS

KW - DIPEPTIDE AMIDES

KW - PROTEIN

KW - DESIGN

KW - POTENT

KW - BENZOFURANS

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SN - 0022-2623

VL - 55

SP - 140

EP - 152

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

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Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

Abstract

Keywords

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Aref#d: 20731. The Biosynthesis of Glycoproteins in Trypanosoma Brucei: Basic and Translational Research

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this

Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Projects

Aref#d: 20731. The Biosynthesis of Glycoproteins in Trypanosoma Brucei: Basic and Translational Research

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this