Author: Alicia Tang ; Michelle Palmer ; Bridget K. Wagner ; Tamara Vital ; Joshiawa Paulk ; Clark Reddy ; Nicholas Donato ; Stuart L. Schreiber ; Steven A. Carr ; Amit Choudhary ; Monica Schenone ; Stephen S. Scully ; Christie Ciarlo ; Morten Lundh ; Jacob Jaffe ; Amedeo Vetere ; Hanshi Sun ; Danny Hung Chieh Chou ; Sean M. Burns ; Eamon Comer ; Patrick W. Faloon ; Paul A. Clemons ; Vlado Dančík ; Rachel Gomez ; Matthew Young ; Mingji Dai

Phenotypic cell-based screening is a powerful approach to small-molecule discovery, but a major challenge of this strategy lies in determining the intracellular target and mechanism of action (MoA) for validated hits. Here, we show that the small-molecule BRD0476, a novel suppressor of pancreatic β-cell apoptosis, inhibits interferon-gamma (IFN-γ)-induced Janus kinase 2 (JAK2) and signal transducer and activation of transcription 1 (STAT1) signaling to promote β-cell survival. However, unlike common JAK-STAT pathway inhibitors, BRD0476 inhibits JAK-STAT signaling without suppressing the kinase activity of any JAK. Rather, we identified the deubiquitinase ubiquitin-specific peptidase 9X (USP9X) as an intracellular target, using a quantitative proteomic analysis in rat β cells. RNAi-mediated and CRISPR/Cas9 knockdown mimicked the effects of BRD0476, and reverse chemical genetics using a known inhibitor of USP9X blocked JAK-STAT signaling without suppressing JAK activity. Site-directed mutagenesis of a putative ubiquitination site on JAK2 mitigated BRD0476 activity, suggesting a competition between phosphorylation and ubiquitination to explain small-molecule MoA. These results demonstrate that phenotypic screening, followed by comprehensive MoA efforts, can provide novel mechanistic insights into ostensibly well-understood cell signaling pathways. Furthermore, these results uncover USP9X as a potential target for regulating JAK2 activity in cellular inflammation.

23 May 2013·Journal of Medicinal ChemistryQ1 · MEDICINE

Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction in β-Cells with Improved Aqueous Solubility

Q1 · MEDICINE

Article

Author: Lundh, Morten ; Scully, Stephen S. ; Perkins, Kedar M. ; Tang, Alicia J. ; Wagner, Bridget K. ; Mosher, Carrie M.

We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced β-cell apoptosis. Herein, we report the synthesis and biological evaluation of 1 and analogues with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogues with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that 1 and analogues inhibit STAT1 signal transduction induced by IFN-γ.

08 Sep 2011·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Synthesis of a Novel Suppressor of β-Cell Apoptosis via Diversity-Oriented Synthesis

Q3 · MEDICINE

Article

Author: Liu, Haibo ; Forbeck, Erin M. ; Gerard, Baudouin ; Faloon, Patrick ; Wagner, Bridget K. ; Pandya, Bhaumik A. ; Suh, Byung-Chul ; Marcaurelle, Lisa A. ; Chou, Danny Hung-Chieh ; Duvall, Jeremy R.

The synthesis of a stereochemically diverse library of medium-sized rings accessible via a 'build/couple/pair' strategy is described. Key aspects of the synthesis include S(N)Ar cycloetherification of a linear amine template to afford eight stereoisomeric 8-membered lactams and subsequent solid-phase diversification of these scaffolds to yield a 6488-membered library. Screening of this compound collection in a cell-based assay for the suppression of cytokine-induced beta-cell apoptosis resulted in the identification of a small-molecule suppressor capable of restoring glucose-stimulated insulin secretion in a rat beta-cell line. The presence of all stereoisomers in the screening collection enabled preliminary determination of the structural and stereochemical requirements for cellular activity, while efficient follow-up chemistry afforded BRD-0476 (probe ML187), which had an approximately three-fold increase in activity. These results demonstrate the utility of diversity-oriented synthesis to probe discovery using cell-based screening, and the importance of including stereochemical diversity in screening collections for the development of stereo/structure-activity relationships.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 1	Preclinical	US	The Broad Institute, Inc.	-
Neoplasms	Preclinical	US	Harvard University	-

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