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Article ; Online: Target engagement approaches for pharmacological evaluation in animal models.

Kath, James E / Baranczak, Aleksandra

Chemical communications (Cambridge, England)

2019 Volume 55, Issue 63, Page(s) 9241–9250

Abstract: The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in ... ...

Abstract	The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials. Broadly speaking, these efforts can be divided between compounds that covalently and reversibly interact with protein targets; recent examples for both categories are discussed for a range of targets, along with their limitations. New, promising technologies are also highlighted, in addition to the application of target engagement determination to new therapeutic modalities.
MeSH term(s)	Animals ; Drug Interactions ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacokinetics ; Models, Animal ; Pharmaceutical Preparations/chemistry ; Pharmaceutical Preparations/metabolism ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacokinetics
Chemical Substances	Enzyme Inhibitors ; Pharmaceutical Preparations ; Protein Kinase Inhibitors
Language	English
Publishing date	2019-07-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/c9cc02824b
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evaluation of Chemically-Cleavable Linkers for Quantitative Mapping of Small Molecule-Cysteinome Reactivity.

Rabalski, Adam J / Bogdan, Andrew R / Baranczak, Aleksandra

ACS chemical biology

2019 Volume 14, Issue 9, Page(s) 1940–1950

Abstract: Numerous reagents have been developed to enable chemical proteomic analysis of small molecule-protein interactomes. However, the performance of these reagents has not been systematically evaluated and compared. Herein, we report our efforts to conduct a ... ...

Abstract	Numerous reagents have been developed to enable chemical proteomic analysis of small molecule-protein interactomes. However, the performance of these reagents has not been systematically evaluated and compared. Herein, we report our efforts to conduct a parallel assessment of two widely used chemically cleavable linkers equipped with dialkoxydiphenylsilane (DADPS linker) and azobenzene (AZO linker) moieties. Profiling a cellular cysteinome using the iodoacetamide alkyne probe demonstrated a significant discrepancy between the experimental results obtained through the application of each of the reagents. To better understand the source of observed discrepancy, we evaluated the key sample preparation steps. We also performed a mass tolerant database search strategy using MSFragger software. This resulted in identifying a previously unreported artifactual modification on the residual mass of the azobenzene linker. Furthermore, we conducted a comparative analysis of enrichment modes using both cleavable linkers. This effort determined that enrichment of proteolytic digests yielded a far greater number of identified cysteine residues than the enrichment conducted prior to protein digest. Inspired by recent studies where multiplexed quantitative labeling strategies were applied to cleavable biotin linkers, we combined this further optimized protocol using the DADPS cleavable linker with tandem mass tag (TMT) labeling to profile the FDA-approved covalent EGFR kinase inhibitor dacomitinib against the cysteinome of an epidermoid cancer cell line. Our analysis resulted in the detection and quantification of over 10,000 unique cysteine residues, a nearly 3-fold increase over previous studies that used cleavable biotin linkers for enrichment. Critically, cysteine residues corresponding to proteins directly as well as indirectly modulated by dacomitinib treatment were identified. Overall, our study suggests that the dialkoxydiphenylsilane linker could be broadly applied wherever chemically cleavable linkers are required for chemical proteomic characterization of cellular proteomes.
MeSH term(s)	Azo Compounds/chemistry ; Biotin/analogs & derivatives ; Cell Line, Tumor ; Cysteine/analysis ; Cysteine/chemistry ; Humans ; Protein Binding ; Proteome/chemistry ; Proteome/metabolism ; Proteomics/methods ; Quinazolinones/metabolism ; Quinazolinones/pharmacology ; Silanes/chemistry
Chemical Substances	Azo Compounds ; Proteome ; Quinazolinones ; Silanes ; dacomitinib (5092U85G58) ; Biotin (6SO6U10H04) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2019-08-29
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.9b00424
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Article ; Online: A current pharmacologic agent versus the promise of next generation therapeutics to ameliorate protein misfolding and/or aggregation diseases.

Baranczak, Aleksandra / Kelly, Jeffery W

Current opinion in chemical biology

2016 Volume 32, Page(s) 10–21

Abstract: The list of protein aggregation-associated degenerative diseases is long and growing, while the portfolio of disease-modifying strategies is very small. In this review and perspective, we assess what has worked to slow the progression of an aggregation- ... ...

Abstract	The list of protein aggregation-associated degenerative diseases is long and growing, while the portfolio of disease-modifying strategies is very small. In this review and perspective, we assess what has worked to slow the progression of an aggregation-associated degenerative disease, covering the underlying mechanism of pharmacologic action and what we have learned about the etiology of the transthyretin amyloid diseases and likely amyloidoses in general. Next, we introduce emerging therapies that should apply more generally to protein misfolding and/or aggregation diseases, approaches that rely on adapting the protein homeostasis or proteostasis network for disease amelioration.
MeSH term(s)	Humans ; Protein Folding ; Proteostasis Deficiencies/drug therapy
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1439176-4
ISSN	1879-0402 ; 1367-5931
ISSN (online)	1879-0402
ISSN	1367-5931
DOI	10.1016/j.cbpa.2016.01.009
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Article: Target engagement approaches for pharmacological evaluation in animal models

Kath, James E / Baranczak, Aleksandra

Chemical communications. 2019 Aug. 1, v. 55, no. 63

2019

Abstract	The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials. Broadly speaking, these efforts can be divided between compounds that covalently and reversibly interact with protein targets; recent examples for both categories are discussed for a range of targets, along with their limitations. New, promising technologies are also highlighted, in addition to the application of target engagement determination to new therapeutic modalities.
Keywords	animal models ; chemical bonding ; chemical compounds ; chemical reactions ; clinical trials ; drug development ; drugs ; mechanism of action ; therapeutics
Language	English
Dates of publication	2019-0801
Size	p. 9241-9250.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/c9cc02824b
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Article ; Online: A Dual-Purpose Bromocoumarin Tag Enables Deep Profiling of the Cellular Cysteinome.

Rabalski, Adam J / Williams, Jon D / McClure, Ryan A / Vasudevan, Anil / Baranczak, Aleksandra

Proteomics

2019 Volume 19, Issue 11, Page(s) e1800433

Abstract: Chemical proteomics enables comprehensive profiling of small molecules in complex proteomes. A critical component to understand the interactome of a small molecule is the precise location on a protein where the interaction takes place. Several approaches ...

Abstract	Chemical proteomics enables comprehensive profiling of small molecules in complex proteomes. A critical component to understand the interactome of a small molecule is the precise location on a protein where the interaction takes place. Several approaches have been developed that take advantage of bio-orthogonal chemistry and subsequent enrichment steps to isolate peptides modified by small molecules. These methods rely on target identification at the level of mass spectrometry making it difficult to interpret an experiment when modified peptides are not identified. Herein, an approach in which fluorescence-triggered two-dimensional chromatography enables the isolation of small molecule-conjugated peptides prior to mass spectrometry analysis is described. In this study, a bromocoumarin moiety has been utilized that fluoresces and generates a distinct isotopic signature to locate and identify modified peptides. Profiling of a cellular cysteinome with the use of a bromocoumarin tag demonstrates that two-dimensional fluorescence-based chromatography separation can enable the identification of proteins containing reactive cysteine residues. Moreover, the method facilitates the interrogation of low abundance proteins with greater depth and sensitivity than a previously reported isotope-targeted approach. Lastly, this workflow enables the identification of small-molecule modified peptides from a protein-of-interest.
MeSH term(s)	Coumarins/chemistry ; Cysteine/analysis ; Fluorescence ; Fluorescent Dyes/chemistry ; Halogenation ; Humans ; K562 Cells ; Peptides/chemistry ; Proteomics/methods ; Tandem Mass Spectrometry/methods
Chemical Substances	Coumarins ; Fluorescent Dyes ; Peptides ; coumarin (A4VZ22K1WT) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2019-05-08
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2032093-0
ISSN	1615-9861 ; 1615-9853
ISSN (online)	1615-9861
ISSN	1615-9853
DOI	10.1002/pmic.201800433
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Zs.A 5386: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.A 1868: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)

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Article: Cascade assembly of the benzo[a]anthraquinone ring system common to the angucycline antibiotics.

Baranczak, Aleksandra / Sulikowski, Gary A

Tetrahedron letters

2012 Volume 53, Issue 11, Page(s) 1345–1346

Abstract: A benzo[a]anthraquinone ring system, common to a group of angucycline antibiotics, has been prepared by a unique cascade of reactions. The reaction sequence was initiated by a Suzuki-Miyaura cross-coupling between a bromoquinone and vinyl boronic ... ...

Abstract	A benzo[a]anthraquinone ring system, common to a group of angucycline antibiotics, has been prepared by a unique cascade of reactions. The reaction sequence was initiated by a Suzuki-Miyaura cross-coupling between a bromoquinone and vinyl boronic anhdyride. The reaction product is proposed to undergo a 6π-electron cyclization triggered by reductive activation of the quinone. The reaction process is proposed to be autocatalytic.
Language	English
Publishing date	2012-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	204287-3
ISSN	1873-3581 ; 0040-4039
ISSN (online)	1873-3581
ISSN	0040-4039
DOI	10.1016/j.tetlet.2011.12.126
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Zs.A 2837: Show issues

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Article ; Online: Synthetic studies directed toward dideoxy lomaiviticinone lead to unexpected 1,2-oxazepine and isoxazole formation.

Baranczak, Aleksandra / Sulikowski, Gary A

Organic letters

2012 Volume 14, Issue 4, Page(s) 1027–1029

Abstract: In the course of studies directed toward the synthesis of dideoxy lomaiviticinone, 3-(nitromethyl)cyclohexenones 2a (X = H) and 2b (X = I) were prepared. The corresponding enolates were reacted with naphthazarin (1) and unexpectedly afforded 1,2- ... ...

Abstract	In the course of studies directed toward the synthesis of dideoxy lomaiviticinone, 3-(nitromethyl)cyclohexenones 2a (X = H) and 2b (X = I) were prepared. The corresponding enolates were reacted with naphthazarin (1) and unexpectedly afforded 1,2-oxazepine 3 and isoxazole 4, respectively. Rationale for their formation is proposed.
MeSH term(s)	Benzoquinones/chemistry ; Catalysis ; Cyclohexanones/chemical synthesis ; Isoxazoles/chemical synthesis ; Molecular Structure ; Oxazepines/chemical synthesis ; Oxidation-Reduction ; Polycyclic Compounds/chemical synthesis
Chemical Substances	Benzoquinones ; Cyclohexanones ; Isoxazoles ; Oxazepines ; Polycyclic Compounds ; dideoxy lomaiviticinone ; quinone (3T006GV98U)
Language	English
Publishing date	2012-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1523-7052
ISSN (online)	1523-7052
DOI	10.1021/ol203390w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Synthetic Studies Directed toward Dideoxy Lomaiviticinone Lead to Unexpected 1,2-Oxazepine and Isoxazole Formation

Baranczak, Aleksandra / Sulikowski Gary A

Organic letters. 2012 Feb. 17, v. 14, no. 4

2012

Abstract	In the course of studies directed toward the synthesis of dideoxy lomaiviticinone, 3-(nitromethyl)cyclohexenones 2a (X = H) and 2b (X = I) were prepared. The corresponding enolates were reacted with naphthazarin (1) and unexpectedly afforded 1,2-oxazepine 3 and isoxazole 4, respectively. Rationale for their formation is proposed.
Keywords	chemical reactions ; chemical structure ; organic compounds
Language	English
Dates of publication	2012-0217
Size	p. 1027-1029.
Publishing place	American Chemical Society
Document type	Article
ISSN	1523-7052
DOI	10.1021%2Fol203390w
Database	NAL-Catalogue (AGRICOLA)

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Article: Cascade assembly of the benz[a]anthraquinone ring system common to the angucycline antibiotics

Baranczak, Aleksandra / Sulikowski, Gary A

Tetrahedron letters. 2012 Mar. 14, v. 53, no. 11

2012

Abstract: A benz[a]anthraquinone ring system, common to a group of angucycline antibiotics, has been prepared by a unique cascade of reactions. The reaction sequence was initiated by a Suzuki–Miyaura cross-coupling between a bromoquinone and vinyl boronic ... ...

Abstract	A benz[a]anthraquinone ring system, common to a group of angucycline antibiotics, has been prepared by a unique cascade of reactions. The reaction sequence was initiated by a Suzuki–Miyaura cross-coupling between a bromoquinone and vinyl boronic anhydride. The reaction product is proposed to undergo a 6π-electron cyclization triggered by reductive activation of the quinone. The reaction process is proposed to be autocatalytic.
Keywords	anthraquinones ; antibiotics ; chemical reactions ; chemical structure
Language	English
Dates of publication	2012-0314
Size	p. 1345-1346.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	204287-3
ISSN	1873-3581 ; 0040-4039
ISSN (online)	1873-3581
ISSN	0040-4039
DOI	10.1016/j.tetlet.2011.12.126
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 2837: Show issues

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Article: Integrated Platform for Expedited Synthesis-Purification-Testing of Small Molecule Libraries.

Baranczak, Aleksandra / Tu, Noah P / Marjanovic, Jasmina / Searle, Philip A / Vasudevan, Anil / Djuric, Stevan W

ACS medicinal chemistry letters

2017 Volume 8, Issue 4, Page(s) 461–465

Abstract: The productivity of medicinal chemistry programs can be significantly increased through the introduction of automation, leading to shortened discovery cycle times. Herein, we describe a platform that consolidates synthesis, purification, quantitation, ... ...

Abstract	The productivity of medicinal chemistry programs can be significantly increased through the introduction of automation, leading to shortened discovery cycle times. Herein, we describe a platform that consolidates synthesis, purification, quantitation, dissolution, and testing of small molecule libraries. The system was validated through the synthesis and testing of two libraries of binders of polycomb protein EED, and excellent correlation of obtained data with results generated through conventional approaches was observed. The fully automated and integrated platform enables batch-supported compound synthesis based on a broad array of chemical transformations with testing in a variety of biochemical assay formats. A library turnaround time of between 24 and 36 h was achieved, and notably, each library synthesis produces sufficient amounts of compounds for further evaluation in secondary assays thereby contributing significantly to the shortening of medicinal chemistry discovery cycles.
Language	English
Publishing date	2017-03-28
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.7b00054
Database	MEDical Literature Analysis and Retrieval System OnLINE

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