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Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis.

ABSTRACT: Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle.

SUBMITTER: Patel G

PROVIDER: S-EPMC3663906 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis.

Patel Gautam G Karver Caitlin E CE Behera Ranjan R Guyett Paul J PJ Sullenberger Catherine C Edwards Peter P Roncal Norma E NE Mensa-Wilmot Kojo K Pollastri Michael P MP

Journal of medicinal chemistry 20130503 10

Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei wit ...[more]

PMID: 23597080

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Project description:Mutacin 1140 belongs to the epidermin group of lantibiotics. Epidermin class lantibiotics are ribosomally synthesized and posttranslationally modified antibiotics with potent activity against Gram-positive bacteria. In particular, this class is effective at targeting drug-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis, and Clostridium difficile A C-terminal S-[(Z)-2-aminovinyl]-d-cysteine (AviCys) residue is derived from a decarboxylation of a terminal cysteine that is involved in lanthionine ring formation. Studies on mutacin 1140 have revealed new insight into the structural importance of the C-terminal AviCys residue. A C-terminal carboxyl analogue of mutacin 1140 was engineered. Capping the C-terminal carboxyl group with a primary amine restores bioactivity and affords a novel opportunity to synthesize new analogues. A C-terminal fluorescein-labeled mutacin 1140 analogue traps lipid II into a large lipid II lantibiotic complex, similar to that observed in vivo for the lantibiotic nisin. A C-terminal carboxyl analogue of mutacin 1140 competitively inhibits the activity of native mutacin 1140 and nisin. The presence of a C-terminal carboxyl group prevents the formation of the large lipid II lantibiotic complexes but does not prevent the binding of the lantibiotic to lipid II.IMPORTANCE This study addressed the importance of the C-terminal S-[(Z)-2-aminovinyl]-d-cysteine (AviCys) residue for antibacterial activity. We have learned that the posttranslational modification for making the AviCys residue is presumably important for the lateral assembly mechanism of activity that traps lipid II into a large complex. The C-terminal carboxyl analogue of this class of lantibiotics is agreeable to the addition of a wide variety of substrates. The addition of fluorescein enabled in vivo visualization of the epidermin class of lantibiotics in action. These results are significant because, as we demonstrate, the presence of the AviCys residue is not essential for bioactivity, but, more importantly, the removal of the carboxyl group is essential. The ability to make a C-terminal carboxyl analogue that is modifiable will facilitate the synthesis of novel analogues of the epidermin class of lantibiotics that can be developed for new applications.

Project description:A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

Dataset Information

Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis.

Publications

Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis.

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