Identification of ML251, a Potent Inhibitor ofT. brucei and T. cruziPhosphofructokinase

Abstract

Human African Trypanosomiasis (HAT) is a severe, often fatal disease caused by the parasitic protist Trypanosoma brucei. The glycolytic pathway has been identified as the sole mechanism for ATP generation in the infective stage of these organisms, and several glycolytic enzymes, phosphofructokinase (PFK) in particular, have shown promise as potential drug targets. Herein, we describe the discovery of ML251, a novel nanomolar inhibitor of T. brucei PFK, and the structure-activity relationships within the series.

Kinases as Druggable Targets in Trypanosomatid Protozoan Parasites

“…Recently, Brimacombe et al screened 330 683 compounds against T. brucei PFK. 102 The para -amidosulfonamide scaffold, typified by 25 (Figure 7 ), was identified as a hit series. A derivative of the antibiotic sulfamethoxazole, 25 was a 0.41 μM inhibitor of TbPFK.…”

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

“…25 The efforts of organizations like the DNDi and Tres Cantos Open Lab Foundation have increased awareness about neglected parasitic diseases, and inspired many new trypanosomiasis drug discovery programs. Most campaigns have focused on either T. brucei 13,[26][27][28][29][30][31][32][33][34][35][36] or T. cruzi; [37][38][39][40][41][42] fewer have involved a concerted effort to discover leads that are effective against both pathogenic species, [43][44][45][46][47][48][49][50][51][52][53] despite the economies of broad-spectrum drug development, especially for neglected diseases.…”

Non-stoichiometric inhibition in integrated lead finding – a literature review

“…right after the primary screen, through readout controls and orthogonal assays. These are in the meantime well established in the field [31,32,34,[84][85][86] and wherever possible should be part of the screening flowchart. However, all of these approaches primarily aim to eliminate compounds interfering with the readout.…”

“…As orthogonal assays are now routinely used in screening campaigns, a complete overview is impossible and only a few selected examples can be cited here. [31][32][33][34] Particularly suitable and widely used are label-free technologies such as mass spectrometry -both in combination with liquid chromatography [21,35] and in the matrix-assisted laser desorption/ionization variant. [36,37] Not only biochemical but also cellular assays suffer from readout interference.…”