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Kozyrev A.,Nanosyn, Inc. | Ethirajan M.,Roswell Park Cancer Institute | Chen P.,University of Houston | Ohkubo K.,Osaka University | And 6 more authors.
Journal of Organic Chemistry | Year: 2012

A series of new bacteriochlorins was synthesized using 13 2-oxo-bacteriopyropheophorbide a (derived from bacteriochlorophyll a) as a starting material, which on reacting with o-phenylenediamine and 1,10-diaminonaphthalene afforded highly conjugated annulated bacteriochlorins with fused quinoxaline, benzimidazole, and perimidine rings, respectively. The absorption spectra of these novel bacteriochlorins demonstrated remarkably red-shifted intense Qy absorption bands observed in the range of 816-850 nm with high molar extinction coefficients (89,900-136,800). Treatment of 132-oxo-bacteriopyropheophorbide a methyl ester with diazomethane resulted in the formation of bacterioverdins containing a fused six-membered methoxy-substituted cyclohexenone (verdin) as an isomeric mixture. The pure isomers which exhibit long-wavelength absorptions in the near-IR region (865-890 nm) are highly stable at room temperature with high reactivity with O 2 at the triplet photoexcited state and favorable redox potential and could be potential candidates for use as photosensitizers in photodynamic therapy (PDT). © 2012 American Chemical Society.


Elkins J.M.,University of Oxford | Fedele V.,University of Oxford | Szklarz M.,University of Oxford | Abdul Azeez K.R.,University of Oxford | And 35 more authors.
Nature Biotechnology | Year: 2016

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome. © 2016 Nature America, Inc. All rights reserved.


PubMed | Medical University of South Carolina, Foundation Medicine, Glaxosmithkline, U.S. National Cancer Institute and 4 more.
Type: Journal Article | Journal: Nature biotechnology | Year: 2016

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.


PubMed | Oregon Health And Science University, Stanford University, University of California at Los Angeles and Nanosyn, Inc.
Type: Journal Article | Journal: Leukemia | Year: 2016

The transcription factor CREB (cAMP Response-Element Binding Protein) is overexpressed in the majority of acute myeloid leukemia (AML) patients, and this is associated with a worse prognosis. Previous work revealed that CREB overexpression augmented AML cell growth, while CREB knockdown disrupted key AML cell functions in vitro. In contrast, CREB knockdown had no effect on long-term hematopoietic stem cell activity in mouse transduction/transplantation assays. Together, these studies position CREB as a promising drug target for AML. To test this concept, a small molecule inhibitor of CREB, XX-650-23, was developed. This molecule blocks a critical interaction between CREB and its required co-activator CBP (CREB Binding Protein), leading to disruption of CREB-driven gene expression. Inhibition of CBP-CREB interaction induced apoptosis and cell-cycle arrest in AML cells, and prolonged survival in vivo in mice injected with human AML cells. XX-650-23 had little toxicity on normal human hematopoietic cells and tissues in mice. To understand the mechanism of XX-650-23, we performed RNA-seq, ChIP-seq and Cytometry Time of Flight with human AML cells. Our results demonstrate that small molecule inhibition of CBP-CREB interaction mostly affects apoptotic, cell-cycle and survival pathways, which may represent a novel approach for AML therapy.


Bradshaw J.M.,Principia BioPharma | McFarland J.M.,Howard Hughes Medical Institute | Paavilainen V.O.,Howard Hughes Medical Institute | Bisconte A.,Principia BioPharma | And 19 more authors.
Nature Chemical Biology | Year: 2015

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo. © 2015 Nature America, Inc. All rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 295.30K | Year: 2014

DESCRIPTION (provided by applicant): We will employ a novel approach to develop unique ALS therapeutics by focusing on drugs that activate a natural cellular protective mechanism, autophagy. Stimulating autophagy is a logical approach to treat the underlying neurodegeneration that causes ALS. It is the prime defense mechanism that neurons have for removing toxic misfolded aggregated proteins, and there is evidence that neurodegeneration of motor neurons (MNs) in ALS is caused by the buildup of toxic, misfolded, aggregated forms of SOD1, TDP43 and FUS. Mutations in these proteins cause familial ALS (fALS), and overexpression or abnormal post-translational modification of these proteins leads to MN degeneration in sporadic ALS (sALS). We will develop drugs that effectively stimulate autophagy in ALS MNs to remove the buildup of toxic proteins to block neurodegeneration and disease progression to treat sALS patients. Our collaborator, Dr. Finkbeiner, previously identified drugs that stimulate autophagy in


PubMed | Howard Hughes Medical Institute, Principia BioPharma and Nanosyn, Inc.
Type: Journal Article | Journal: Nature chemical biology | Year: 2015

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Brutons tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates residence time by design, the ability to modulate and improve the duration of target engagement in vivo.


PubMed | Nanosyn, Inc.
Type: Journal Article | Journal: The Journal of organic chemistry | Year: 2012

A series of new bacteriochlorins was synthesized using 13(2)-oxo-bacteriopyropheophorbide a (derived from bacteriochlorophyll a) as a starting material, which on reacting with o-phenylenediamine and 1,10-diaminonaphthalene afforded highly conjugated annulated bacteriochlorins with fused quinoxaline, benzimidazole, and perimidine rings, respectively. The absorption spectra of these novel bacteriochlorins demonstrated remarkably red-shifted intense Q(y) absorption bands observed in the range of 816-850 nm with high molar extinction coefficients (89,900-136,800). Treatment of 13(2)-oxo-bacteriopyropheophorbide a methyl ester with diazomethane resulted in the formation of bacterioverdins containing a fused six-membered methoxy-substituted cyclohexenone (verdin) as an isomeric mixture. The pure isomers which exhibit long-wavelength absorptions in the near-IR region (865-890 nm) are highly stable at room temperature with high reactivity with O(2) at the triplet photoexcited state and favorable redox potential and could be potential candidates for use as photosensitizers in photodynamic therapy (PDT).


Nanosyn, Inc. | Entity website

Chemistry Technology Chemistry on Demand is a sophisticated technological platform based on Nanosyn's patented techniques which include proprietary methodology, know-how, chemical synthesis, software and instrumentation designed to generate novel, pure, and well characterized compounds. The technology consists of a matrix of highly integrated, but independent components, allowing for maximum flexibility in the synthesis of novel molecules with improved MedChem properties providing you with compounds when you need them ...


Nanosyn, Inc. | Entity website

Proprietary Library Development Proprietary Library Development - Plug and Play Libraries Don't screen the same compound libraries as everyone else! Nanosyn can design and synthesize libraries which will better suit your needs. We can provide libraries of Lead Like compounds against your targets using proprietary scaffolds and synthons, allowing you to proceed to later stage development at a much faster rate ...

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