A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors

Justin R. Harrison; Stephen Brand; Victoria Smith; David A. Robinson; Stephen Thompson; Alasdair Smith; Kenneth Davies; Ngai Mok; Leah S. Torrie; Iain Collie; Irene Hallyburton; Suzanne Norval; Frederick R. C. Simeons; Laste Stojanovski; Julie A. Frearson; Ruth Brenk; Paul G. Wyatt; Ian H. Gilbert; Kevin D. Read

doi:10.1021/acs.jmedchem.8b00884

A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors

Justin R. Harrison, Stephen Brand, Victoria Smith, David A. Robinson, Stephen Thompson, Alasdair Smith, Kenneth Davies, Ngai Mok, Leah S. Torrie, Iain Collie, Irene Hallyburton, Suzanne Norval, Frederick R. C. Simeons, Laste Stojanovski, Julie A. Frearson, Ruth Brenk, Paul G. Wyatt, Ian H. Gilbert (Lead / Corresponding author), Kevin D. Read (Lead / Corresponding author)

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Abstract

Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.

Original language	English
Pages (from-to)	8374–8389
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00884
Publication status	Published - 12 Sep 2018

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Gilbert, Ian

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Harrison, J. R., Brand, S., Smith, V., Robinson, D. A., Thompson, S., Smith, A., Davies, K., Mok, N., Torrie, L. S., Collie, I., Hallyburton, I., Norval, S., Simeons, F. R. C., Stojanovski, L., Frearson, J. A., Brenk, R., Wyatt, P. G., Gilbert, I. H., & Read, K. D. (2018). A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors. Journal of Medicinal Chemistry, 61(18), 8374–8389. https://doi.org/10.1021/acs.jmedchem.8b00884

Harrison, Justin R. ; Brand, Stephen ; Smith, Victoria ; Robinson, David A. ; Thompson, Stephen ; Smith, Alasdair ; Davies, Kenneth ; Mok, Ngai ; Torrie, Leah S. ; Collie, Iain ; Hallyburton, Irene ; Norval, Suzanne ; Simeons, Frederick R. C. ; Stojanovski, Laste ; Frearson, Julie A. ; Brenk, Ruth ; Wyatt, Paul G. ; Gilbert, Ian H. ; Read, Kevin D. / A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 18. pp. 8374–8389.

@article{0fde8ed0e39f4900a90525e754e4c70a,

title = "A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors",

abstract = "Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.",

author = "Harrison, {Justin R.} and Stephen Brand and Victoria Smith and Robinson, {David A.} and Stephen Thompson and Alasdair Smith and Kenneth Davies and Ngai Mok and Torrie, {Leah S.} and Iain Collie and Irene Hallyburton and Suzanne Norval and Simeons, {Frederick R. C.} and Laste Stojanovski and Frearson, {Julie A.} and Ruth Brenk and Wyatt, {Paul G.} and Gilbert, {Ian H.} and Read, {Kevin D.}",

note = "Funding for this work was provided by the Wellcome Trust (Grants WT077705 and WT094090 and Strategic Award WT083481).",

year = "2018",

month = sep,

day = "12",

doi = "10.1021/acs.jmedchem.8b00884",

language = "English",

volume = "61",

pages = "8374–8389",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "18",

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Harrison, JR, Brand, S, Smith, V, Robinson, DA , Thompson, S, Smith, A, Davies, K, Mok, N, Torrie, LS, Collie, I, Hallyburton, I, Norval, S , Simeons, FRC , Stojanovski, L, Frearson, JA, Brenk, R, Wyatt, PG , Gilbert, IH & Read, KD 2018, 'A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors', Journal of Medicinal Chemistry, vol. 61, no. 18, pp. 8374–8389. https://doi.org/10.1021/acs.jmedchem.8b00884

A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors. / Harrison, Justin R.; Brand, Stephen; Smith, Victoria; Robinson, David A.; Thompson, Stephen; Smith, Alasdair; Davies, Kenneth; Mok, Ngai; Torrie, Leah S.; Collie, Iain; Hallyburton, Irene; Norval, Suzanne ; Simeons, Frederick R. C.; Stojanovski, Laste; Frearson, Julie A.; Brenk, Ruth; Wyatt, Paul G.; Gilbert, Ian H. (Lead / Corresponding author); Read, Kevin D. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 61, No. 18, 12.09.2018, p. 8374–8389.

Research output: Contribution to journal › Article

TY - JOUR

T1 - A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors

AU - Harrison, Justin R.

AU - Brand, Stephen

AU - Smith, Victoria

AU - Robinson, David A.

AU - Thompson, Stephen

AU - Smith, Alasdair

AU - Davies, Kenneth

AU - Mok, Ngai

AU - Torrie, Leah S.

AU - Collie, Iain

AU - Hallyburton, Irene

AU - Norval, Suzanne

AU - Simeons, Frederick R. C.

AU - Stojanovski, Laste

AU - Frearson, Julie A.

AU - Brenk, Ruth

AU - Wyatt, Paul G.

AU - Gilbert, Ian H.

AU - Read, Kevin D.

N1 - Funding for this work was provided by the Wellcome Trust (Grants WT077705 and WT094090 and Strategic Award WT083481).

PY - 2018/9/12

Y1 - 2018/9/12

N2 - Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.

AB - Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.

U2 - 10.1021/acs.jmedchem.8b00884

DO - 10.1021/acs.jmedchem.8b00884

M3 - Article

C2 - 30207721

VL - 61

SP - 8374

EP - 8389

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 18

ER -