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

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

SN - 0022-2623

VL - 61

SP - 8374

EP - 8389

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -