- Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2
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By screening a focused library of kinase inhibitor analogues in a phenotypic co-culture assay for angiogenesis inhibition, we identified an aminotriazine that acts as a cytostatic nanomolar inhibitor. However, this aminotriazine was found to be completely inactive in a whole-kinome profiling assay. To decipher its mechanism of action, we used the online target prediction tool PPB2 (http://ppb2.gdb.tools), which suggested lysophosphatidic acid acyltransferase β (LPAAT-β) as a possible target for this aminotriazine as well as several analogues identified by structure–activity relationship profiling. LPAAT-β inhibition (IC50 ≈15 nm) was confirmed in a biochemical assay and by its effects on cell proliferation in comparison with a known LPAAT-β inhibitor. These experiments illustrate the value of target-prediction tools to guide target identification for phenotypic screening hits and significantly expand the rather limited pharmacology of LPAAT-β inhibitors.
- Poirier, Marion,Awale, Mahendra,Roelli, Matthias A.,Giuffredi, Guy T.,Ruddigkeit, Lars,Evensen, Lasse,Stooss, Amandine,Calarco, Serafina,Lorens, James B.,Charles, Roch-Philippe,Reymond, Jean-Louis
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supporting information
p. 224 - 236
(2018/12/13)
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- Synthesis and antiviral activity of benzimidazolyl-and triazolyl-1,3,5- triazines
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A novel series of 1,3,5-triazine analogs was successfully synthesized through conjugation with benzimidazole or 1,2,4-triazole derivatives via a methylenethio linker. The new analogs were in vitro evaluated against HSV-1 in Vero cells; among these analogs, two compounds exhibited good effect in inhibiting HSV-1 replication (for compound 5p: EC50 = 3.5 μg/ml, SI = 358; for compound 5r: EC50 = 5.0 μg/ml, SI = 300) in comparison to acyclovir. Springer Science+Business Media, LLC 2011.
- Maarouf, Azza R.,Farahat, Abdelbasset A.,Selim, Khalid B.,Eisa, Hassan M.
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p. 703 - 710
(2012/09/22)
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- Synthesis and in vitro evaluation of 2,4-diamino-1,3,5-triazine derivatives as neuronal voltage-gated sodium channel blockers
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Neuronal sodium channels blockers interfere with ion flux and have been used for managing neuropathic pain, epilepsy, and cerebral ischemic disorders. In the current study, four groups of 2,4-diamino-1,3,5-triazine derivatives were synthesized and investigated for their neuronal sodium channels binding activity. 5-Aryl-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamines (4a-4j) were found to have the best neuronal sodium binding activity among the four groups of triazines evaluated. Derivatives 4a-4j blocked the sodium channels with IC50 values ranged from 4.0 to 14.7 μM. The result from this study showed that analogues of 2,4-diamino-1,3,5-triazines could be used as leads for the discovery of neuronal sodium channels blockers for managing central nervous system related disorders.
- Ma, Xiang,Poon, Thong-Yuen,Wong, Peter Tsun Hon,Chui, Wai-Keung
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supporting information; experimental part
p. 5644 - 5647
(2010/04/26)
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