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Bioorganic & medicinal chemistry letters (1)
Journal of Biomolecular Screening (1)
Brown, Brock (2)
Garcia, Xochella (2)
Sergienko, Eduard (2)
Cashman, John R. (1)
Ghirmai, Senait (1)
Hurder, Andrew (1)
MacDonald, Mary (1)
Millán, José Luis (1)
Narisawa, Sonoko (1)
Okolotowicz, Karl J. (1)
Reed, John C. (1)
Su, Ying (1)
Zhai, Dayong (1)
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Identification and Characterization of Novel Tissue-Nonspecific Alkaline Phosphatase Inhibitors with Diverse Modes of Action
Millán, José Luis
Journal of Biomolecular Screening
Tissue-nonspecific alkaline phosphatase (TNAP) plays a major role in maintaining a ratio of phosphate to inorganic pyrophosphate (Pi/PPi) in biological fluids that is conducive to controlled skeletal mineralization while preventing inappropriate ectopic calcification. Medial calcification associated with Enpp1 or Ank deficiency or with end–stage renal disease is associated with an increase in TNAP activity in arteries that leads to reduced levels of PPi and increased vascular calcification. Here, we describe in detail a high-throughput screening (HTS) campaign to identify inhibitors of TNAP, performed within the Molecular Library Screening Center Network (MLSCN). A homogeneous luminescent TNAP assay was developed and optimized for identification of compounds with diverse mechanism of action (MOA). The MLSCN compound collection, containing 64,394 molecules at the time of screening, was tested in the assay. Several novel inhibitory scaffold classes were identified and demonstrated to have diverse selectivity and mode of inhibition (MOI) profiles. Representatives of the novel scaffolds exhibited nanomolar potency surpassing the inhibitors known to date.
This paper sets a successful example in which pharmacologically active compounds, with outstanding selectivity in a panel of more than 200 assays, are identified from high throughput screening. Integral to the success of the project were a well-designed compound collection, an industrial-level screening facility and a deep knowledge of target biology that were brought together through the NIH-sponsored Roadmap Initiative.
NIH Roadmap Initiatives; MLSCN; TNAP inhibitors; diverse MOA; compound selectivity
Inhibition of Bfl-1 with N-Aryl Maleimides
Cashman, John R.
Okolotowicz, Karl J.
Reed, John C.
Bioorganic & medicinal chemistry letters
High throughput screening of 66,000 compounds using competitive binding of peptides comprising the BH3 domain to anti-apoptotic Bfl-1 led to the identification of fourteen validated “hits” as inhibitors of Bfl-1. N-Aryl maleimide 1 was among the validated “hits”. A chemical library encompassing over 280 analogs of 1 was prepared following a two-step synthesis. Structure-activity studies for inhibition of Bfl-1 by analogs of N-aryl maleimide 1 revealed a preference for electron-withdrawing substituents in the N-aryl ring and hydrophilic amines appended to the maleimide core. Inhibitors of Bfl-1 are potential development candidates for anti-cancer therapeutics.
Bfl-1 inhibitors; N-aryl maleimides; high-throughput screening; anti-cancer agents
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