ORCID Profile
0000-0003-4151-9944
Current Organisations
Brigham and Women's Hospital
,
Mayo Clinic
,
Carleton College
,
National Center for Advancing Translational Sciences
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Publisher: American Chemical Society (ACS)
Date: 02-03-2020
Publisher: American Chemical Society (ACS)
Date: 29-06-2019
DOI: 10.1021/ACS.JMEDCHEM.9B00665
Abstract: A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC
Publisher: Springer Science and Business Media LLC
Date: 13-03-2023
DOI: 10.1038/S41467-023-36829-X
Abstract: Robust, generalizable approaches to identify compounds efficiently with undesirable mechanisms of action in complex cellular assays remain elusive. Such a process would be useful for hit triage during high-throughput screening and, ultimately, predictive toxicology during drug development. Here we generate cell painting and cellular health profiles for 218 prototypical cytotoxic and nuisance compounds in U-2 OS cells in a concentration-response format. A ersity of compounds that cause cellular damage produces bioactive cell painting morphologies, including cytoskeletal poisons, genotoxins, nonspecific electrophiles, and redox-active compounds. Further, we show that lower quality lysine acetyltransferase inhibitors and nonspecific electrophiles can be distinguished from more selective counterparts. We propose that the purposeful inclusion of cytotoxic and nuisance reference compounds such as those profiled in this resource will help with assay optimization and compound prioritization in complex cellular assays like cell painting.
Publisher: Springer Science and Business Media LLC
Date: 21-07-2015
Publisher: Wiley
Date: 14-06-2017
DOI: 10.1111/FAF.12224
Publisher: Springer Science and Business Media LLC
Date: 19-12-2017
DOI: 10.1038/S41598-017-17861-6
Abstract: Glutathione transferase Omega 1 (GSTO1-1) is an atypical GST reported to play a pro-inflammatory role in response to LPS. Here we show that genetic knockout of Gsto1 alters the response of mice to three distinct inflammatory disease models. GSTO1-1 deficiency ameliorates the inflammatory response stimulated by LPS and attenuates the inflammatory impact of a high fat diet on glucose tolerance and insulin resistance. In contrast, GSTO1-1 deficient mice show a more severe inflammatory response and increased escape of bacteria from the colon into the lymphatic system in a dextran sodium sulfate mediated model of inflammatory bowel disease. These responses are similar to those of TLR4 and MyD88 deficient mice in these models and confirm that GSTO1-1 is critical for a TLR4-like pro-inflammatory response in vivo . In wild-type mice, we show that a small molecule inhibitor that covalently binds in the active site of GSTO1-1 can be used to ameliorate the inflammatory response to LPS. Our findings demonstrate the potential therapeutic utility of GSTO1-1 inhibitors in the modulation of inflammation and suggest their possible application in the treatment of a range of inflammatory conditions.
Publisher: Springer Science and Business Media LLC
Date: 15-11-2017
DOI: 10.1038/S41467-017-01657-3
Abstract: Many compounds with potentially reactive chemical motifs and poor physicochemical properties are published as selective modulators of biomolecules without sufficient validation and then propagated in the scientific literature as useful chemical probes. Several histone acetyltransferase (HAT) inhibitors with these liabilities are now routinely used to probe epigenetic pathways. We profile the most commonly used HAT inhibitors and confirm that the majority of them are nonselective interference compounds. Most (15 out of 23, 65%) of the inhibitors are flagged by ALARM NMR, an industry-developed counter-screen for promiscuous compounds. Biochemical counter-screens confirm that most of these compounds are either thiol-reactive or aggregators. Selectivity panels show many of these compounds modulate unrelated targets in vitro, while several also demonstrate nonspecific effects in cell assays. These data demonstrate the usefulness of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many widely used, but insufficiently validated, compounds employed in chemical biology.
Publisher: American Chemical Society (ACS)
Date: 04-02-2019
DOI: 10.1021/ACS.JMEDCHEM.8B01799
Abstract: A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC
Publisher: Elsevier BV
Date: 03-2021
Publisher: American Chemical Society (ACS)
Date: 13-04-2018
DOI: 10.1021/ACS.JMEDCHEM.8B00318
Abstract: Early stage drug discovery reporting on relatively new or difficult targets is often associated with insufficient hit triage. Literature reviews of such targets seldom delve into the detail required to critically analyze the associated screening hits reported. Here we take the enzyme glutathione transferase omega-1 (GSTO1-1) as an ex le of a relatively difficult target and review the associated literature involving small-molecule inhibitors. As part of this process we deliberately pay closer-than-usual attention to assay interference and hit quality aspects. We believe this Perspective will be a useful guide for future development of GSTO1-1 inhibitors, as well serving as a template for future review formats of new or difficult targets.
Publisher: Springer Science and Business Media LLC
Date: 20-10-2015
Publisher: American Chemical Society (ACS)
Date: 27-02-2020
Location: United States of America
No related grants have been discovered for Jayme Dahlin.