N-Myristoyltransferase as a drug target: a (chemical) space odyssey
File(s)
Author(s)
Bell, Andy
Type
Thesis
Abstract
Previous research has provided pre-clinical validation for inhibition of the enzyme N-myristoyltransferase (NMT) target as a novel treatment of fungal and parasitic infections. This thesis describes the discovery of novel NMT inhibitor series derived from high-throughput screens (HTS) of the Pfizer compound collection against NMTs from both Leishmania donovani and Plasmodium falciparum. The further development of two series using structure-based drug design will be discussed, culminating in a series of compounds with efficacy in a mouse malaria model.
Following the initial HTS, the hits were triaged based on the orthogonal attributes of structural diversity of each series of analogues; synthetic ease; orthologue selectivity; and estimated ligand efficiency. Iterative screening resulted in a master set that was further triaged through dose-response assays, including selectivity screening against both human NMTs. Eight novel series of NMT inhibitors, half selective for Leishmania and half for Plasmodium NMTs were approved for disclosure by Pfizer.
One Leishmania-selective series, based on a thienopyrimidine template, was selected for further development based on a physicochemical hypothesis for achieving cell-based activity. Synthesis of a close analogue of the HTS hit provided validation of the series, which was further developed through the iterative synthesis and testing. The key objective of greatly improved activity in the Leishmania cell-based assays was not achieved.
Development of a Plasmodium-selective series of aminomethylindazoles was more successful. Co-crystallisation of a close analogue of the screening hit demonstrated an orthogonal binding mode to the previously published quinoline series. Use of a fragment-linking approach enabled the design and synthesis of novel, highly potent inhibitors with balanced activity against three Plasmodium spp. NMTs, while retaining selectivity over both human NMTs. Excellent translation into cell-based activity was achieved, resulting in several lead compounds with efficacy in a mouse malaria model following both intraperitoneal and oral dosing.
Following the initial HTS, the hits were triaged based on the orthogonal attributes of structural diversity of each series of analogues; synthetic ease; orthologue selectivity; and estimated ligand efficiency. Iterative screening resulted in a master set that was further triaged through dose-response assays, including selectivity screening against both human NMTs. Eight novel series of NMT inhibitors, half selective for Leishmania and half for Plasmodium NMTs were approved for disclosure by Pfizer.
One Leishmania-selective series, based on a thienopyrimidine template, was selected for further development based on a physicochemical hypothesis for achieving cell-based activity. Synthesis of a close analogue of the HTS hit provided validation of the series, which was further developed through the iterative synthesis and testing. The key objective of greatly improved activity in the Leishmania cell-based assays was not achieved.
Development of a Plasmodium-selective series of aminomethylindazoles was more successful. Co-crystallisation of a close analogue of the screening hit demonstrated an orthogonal binding mode to the previously published quinoline series. Use of a fragment-linking approach enabled the design and synthesis of novel, highly potent inhibitors with balanced activity against three Plasmodium spp. NMTs, while retaining selectivity over both human NMTs. Excellent translation into cell-based activity was achieved, resulting in several lead compounds with efficacy in a mouse malaria model following both intraperitoneal and oral dosing.
Version
Open Access
Date Issued
2015-07
Date Awarded
2015-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Tate, Edward
Leatherbarrow, Robin
Smith, Deborah
Sponsor
Engineering and Physical Sciences Research Council
Medical Research Council (Great Britain)
Grant Number
CHTP_G01955
CHBBC_P20559
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)