Repurposing human Aurora kinase inhibitors as leads for anti-protozoan drug discovery

Patel, Gautam; Roncal, Norma; Lee, Patricia; Leed, Susan E.; Erath, Jessey; Rodrı́guez, Ana; Sciotti, Richard J.; Pollastri, Michael P.

doi:10.1039/c4md00045e

Cited by 44 publications

(47 citation statements)

References 14 publications

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“…We have previously reported the value of screening our libraries against multiple kinetoplastid and protozoan parasites [14, 34]. Most importantly, our cross-screening campaign of lapatinib-derived analogs has produced multiple active compounds against one or more parasites in a single library [15].…”

Section: Resultsmentioning

confidence: 99%

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Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

Woodring

Bachovchin

Brady

et al. 2017

European Journal of Medicinal Chemistry

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Human African trypanosomiasis (HAT) is a deadly disease in need of new chemotherapeutics that can cross into the central nervous system. We previously reported the discovery of 2 (NEU-617), a small molecule with activity against T. brucei bloodstream proliferation. Further optimization of 2 to improve the physicochemical properties (LogP, LLE,[1] and MPO score)[2] have led us to twelve sub-micromolar compounds, most importantly the headgroup variants 9i and 9j, and the linker variant 18. Although these 3 compounds had reduced potency compared to 2, they all had improved LogP, LLE and MPO scores. Cross-screening these analogs against other protozoan parasites uncovered 9o with potent activity towards T. brucei, T. cruzi and L. major, while four others compounds (17, 18, 21, 26) showed activity towards P. falciparum D6. This reinforces the effectiveness of lead repurposing for the discovery of new protozoan disease therapeutics.

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Section: Resultsmentioning

confidence: 99%

“…The protocols for the biological assays of Trypanosoma brucei , Trypanosoma cruzi , Leishmania major amastigotes and promastigotes, Plasmodium falciparum D6, W2, C235, and HepG2 toxicity were performed as previously described [34]. …”

Section: Methodsmentioning

confidence: 99%

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

Woodring

Bachovchin

Brady

et al. 2017

European Journal of Medicinal Chemistry

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“…3-8 Launching new antiparasitic drug discovery efforts by redirecting inhibitors of human drug targets that are homologous to essential parasite targets or pathways can facilitate rapid development of structure-activity relationships (SAR), and accelerate “hit” optimization.…”

Section: Introductionmentioning

confidence: 99%

“…8 In addition to the screening of new compounds against T. brucei, compounds were screened against the kinetoplastid parasites Leishmania major (causative agent of cutaneous leishmaniasis) and T. cruzi (which causes Chagas disease), as well as the malaria-causing parasite Plasmodium falciparum . In this report we disclose the results of our efforts to prepare and test thienopyrimidine-based inhibitors, matching the “tail” replacements explored in the previous study that led to compound 2 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria

et al. 2015

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Target repurposing is a proven method for finding new lead compounds that target Trypanosoma brucei, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog 2 with excellent potency against T. brucei (EC50 = 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound 11e to have an EC50 of 84 nM against T. brucei cells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas’ disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies for T. cruzi (4j) and Plasmodium falciparum (11j) were discovered, along with an analog with considerable potency against Leishmania major amastigotes (4e). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites.

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“…Despite this, since 2010 cases of HAT have been reported in over 20 countries in sub‐Saharan Africa, and poses a potential risk for a severe epidemic outbreak . With no current vaccine and access to appropriate facilities for early diagnosis remaining a challenge, the maintenance of a healthy pipeline of candidate molecules to support the discovery of Fexinidazole remains an area of critical importance in neglected tropical disease (NTD) drug discovery …”

Section: Introductionmentioning

confidence: 99%

Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents

et al. 2019

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Recently we reported the results of a screen of the Pathogen Box in which we identified 4‐(2‐amino‐5‐(4‐(methylsulfonyl) phenyl) pyridin‐3‐yl)‐2‐methoxyphenol (MMV010576, 1) as our priority antitrypanosomal hit. This compound had previously been identified as a potent and selective antiplasmodial agent, where a focused optimization campaign, resulted in a medium‐sized library of compounds, with favorable drug‐like properties, one of which (MMV048, 2, 5‐(4‐(methylsulfonyl)phenyl)‐6′‐(trifluoromethyl)‐[3,3′‐bipyridin]‐2‐amine) is currently undergoing clinical trials for malaria. Accordingly, we investigated this library, in order to elucidate structural activity relationship details of this class of compounds as inhibitors of Trypanosoma brucei. Our study has identified several structural features important for antitrypanosomal activity, which are distinct from those required for antiplasmodial activity. Results from this study can be exploited to develop potent antitrypanosomal agents.

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Repurposing human Aurora kinase inhibitors as leads for anti-protozoan drug discovery

Cited by 44 publications

References 14 publications

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria

Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents

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