14 research outputs found
Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space
Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (ā)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening
Canvass: a crowd-sourced, natural-product screening library for exploring biological space
NCATS thanks Dingyin Tao for assistance with compound characterization. This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331). J.C. acknowledges support from the Fogarty International Center, NIH (TW009872). P.A.C. acknowledges support from the National Cancer Institute (NCI), NIH (R01 CA158275), and the NIH/National Institute of Aging (P01 AG012411). N.K.G. acknowledges support from NSF (CHE-1464898). B.C.G. thanks the support of NSF (RUI: 213569), the Camille and Henry Dreyfus Foundation, and the Arnold and Mabel Beckman Foundation. C.C.H. thanks the start-up funds from the Scripps Institution of Oceanography for support. J.N.J. acknowledges support from NIH (GM 063557, GM 084333). A.D.K. thanks the support from NCI, NIH (P01CA125066). D.G.I.K. acknowledges support from the National Center for Complementary and Integrative Health (1 R01 AT008088) and the Fogarty International Center, NIH (U01 TW00313), and gratefully acknowledges courtesies extended by the Government of Madagascar (Ministere des Eaux et Forets). O.K. thanks NIH (R01GM071779) for financial support. T.J.M. acknowledges support from NIH (GM116952). S.M. acknowledges support from NIH (DA045884-01, DA046487-01, AA026949-01), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256), and NCI, NIH, through a Cancer Center Support Grant (P30 CA008748). K.N.M. thanks the California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board for support. B.T.M. thanks Michael Mullowney for his contribution in the isolation, elucidation, and submission of the compounds in this work. P.N. acknowledges support from NIH (R01 GM111476). L.E.O. acknowledges support from NIH (R01-HL25854, R01-GM30859, R0-1-NS-12389). L.E.B., J.K.S., and J.A.P. thank the NIH (R35 GM-118173, R24 GM-111625) for research support. F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC) for financial support. I.S. thanks the University of Oklahoma Startup funds for support. J.T.S. acknowledges support from ACS PRF (53767-ND1) and NSF (CHE-1414298), and thanks Drs. Kellan N. Lamb and Michael J. Di Maso for their synthetic contribution. B.S. acknowledges support from NIH (CA78747, CA106150, GM114353, GM115575). W.S. acknowledges support from NIGMS, NIH (R15GM116032, P30 GM103450), and thanks the University of Arkansas for startup funds and the Arkansas Biosciences Institute (ABI) for seed money. C.R.J.S. acknowledges support from NIH (R01GM121656). D.S.T. thanks the support of NIH (T32 CA062948-Gudas) and PhRMA Foundation to A.L.V., NIH (P41 GM076267) to D.S.T., and CCSG NIH (P30 CA008748) to C.B. Thompson. R.E.T. acknowledges support from NIGMS, NIH (GM129465). R.J.T. thanks the American Cancer Society (RSG-12-253-01-CDD) and NSF (CHE1361173) for support. D.A.V. thanks the Camille and Henry Dreyfus Foundation, the National Science Foundation (CHE-0353662, CHE-1005253, and CHE-1725142), the Beckman Foundation, the Sherman Fairchild Foundation, the John Stauffer Charitable Trust, and the Christian Scholars Foundation for support. J.W. acknowledges support from the American Cancer Society through the Research Scholar Grant (RSG-13-011-01-CDD). W.M.W.acknowledges support from NIGMS, NIH (GM119426), and NSF (CHE1755698). A.Z. acknowledges support from NSF (CHE-1463819). (Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH); CHE-1665145 - NSF; CHE-1665331 - NSF; CHE-1464898 - NSF; RUI: 213569 - NSF; CHE-1414298 - NSF; CHE1361173 - NSF; CHE1755698 - NSF; CHE-1463819 - NSF; GM126221 - NIH; 5R01GM110131 - NIH; GM 063557 - NIH; GM 084333 - NIH; R01GM071779 - NIH; GM116952 - NIH; DA045884-01 - NIH; DA046487-01 - NIH; AA026949-01 - NIH; R01 GM111476 - NIH; R01-HL25854 - NIH; R01-GM30859 - NIH; R0-1-NS-12389 - NIH; R35 GM-118173 - NIH; R24 GM-111625 - NIH; CA78747 - NIH; CA106150 - NIH; GM114353 - NIH; GM115575 - NIH; R01GM121656 - NIH; T32 CA062948-Gudas - NIH; P41 GM076267 - NIH; R01GM114061 - NIGMS, NIH; R15GM116032 - NIGMS, NIH; P30 GM103450 - NIGMS, NIH; GM129465 - NIGMS, NIH; GM119426 - NIGMS, NIH; TW009872 - Fogarty International Center, NIH; U01 TW00313 - Fogarty International Center, NIH; R01 CA158275 - National Cancer Institute (NCI), NIH; P01 AG012411 - NIH/National Institute of Aging; Camille and Henry Dreyfus Foundation; Arnold and Mabel Beckman Foundation; Scripps Institution of Oceanography; P01CA125066 - NCI, NIH; 1 R01 AT008088 - National Center for Complementary and Integrative Health; W81XWH-17-1-0256 - Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program; P30 CA008748 - NCI, NIH, through a Cancer Center Support Grant; California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board; American Lebanese Syrian Associated Charities (ALSAC); University of Oklahoma Startup funds; 53767-ND1 - ACS PRF; PhRMA Foundation; P30 CA008748 - CCSG NIH; RSG-12-253-01-CDD - American Cancer Society; RSG-13-011-01-CDD - American Cancer Society; CHE-0353662 - National Science Foundation; CHE-1005253 - National Science Foundation; CHE-1725142 - National Science Foundation; Beckman Foundation; Sherman Fairchild Foundation; John Stauffer Charitable Trust; Christian Scholars Foundation)Published versionSupporting documentatio
Diiodoindium(III) Cation, InI<sub>2</sub><sup>+</sup>, a Potent Yneophile. Generation and Application to Cationic Cyclization by Selective ĻāActivation of Cī¼C
The removal of the iodide ion from
indium triiodide by means of
reactive AgĀ(I) salts leads to the formation of the highly reactive
ligandless cation InI<sub>2</sub><sup>+</sup>, which is unusual in
having two vacant low-lying p-orbitals. This bivalent Lewis acidity
leads to an especially high affinity for the two orthogonal Ļ-bonds
of carbonācarbon triple bonds. Consequently, the double-coordinating
InI<sub>2</sub><sup>+</sup> is an especially effective reagent for
the selective activation of Cī¼C and the catalytic initiation
of cationic cyclization processes. A number of such reactions are
described to demonstrate synthetic utility
Reversal of the Importance of Steric and Electronic Effects in the Base-Promoted Ī±āSilylation of Sulfides
Lithiation
of Ī±āC-H groups in organic substrates by
RLi or R<sub>2</sub>NLi followed by silylation with Rā²<sub>3</sub>SiCl generally provides analogous products regardless of the
Rā² group of Rā²<sub>3</sub>SiCl. A striking exception
using 3,4-benzothiophane as substrate depending on whether Rā²
is methyl, phenyl, or isopropyl is demonstrated. With Rā² =
Me or Ph, the geminal Ī±,Ī±-bis-silylated products result
whereas with <i>i</i>-Pr<sub>3</sub>SiCl the <i>trans</i>-Ī±,Ī±ā²-bis-silylated sulfide is formed. The latter
pathway provides ready access to the <i>C</i><sub>2</sub>-symmetric enantiomers of <i>trans</i>-2,5-bisĀ(triisopropylsilyl)-3,4-benzothiophane
Selective Formation of Six-Membered Oxa- and Carbocycles by the In(III)-Activated Ring Closure of Acetylenic Substrates
Fifteen examples are disclosed of efficient In(III)-catalyzed six-membered ring closure leading to bi-, tri-, and tetracyclic products
Discovery of Novel Small-Molecule Scaffolds for the Inhibition and Activation of WIP1 Phosphatase from a RapidFire Mass Spectrometry High-Throughput Screen
Wild-type
P53-induced phosphatase 1 (WIP1), also known as PPM1D or PP2CĪ“, is a serine/threonine protein phosphatase
induced by P53 after genotoxic stress. WIP1 inhibition has been proposed
as a therapeutic strategy for P53 wild-type cancers in which it is
overexpressed, but this approach would be ineffective in P53-negative
cancers. Furthermore, there are several cancers with mutated P53 where
WIP1 acts as a tumor suppressor. Therefore, activating WIP1 phosphatase
might also be a therapeutic strategy, depending on the P53 status.
To date, no specific, potent WIP1 inhibitors with appropriate pharmacokinetic
properties have been reported, nor have WIP1-specific activators.
Here, we report the discovery of new WIP1 modulators from a high-throughput
screen (HTS) using previously described orthogonal biochemical assays
suitable for identifying both inhibitors and activators. The primary
HTS was performed against a library of 102āÆ277 compounds at
a single concentration using a RapidFire mass spectrometry assay.
Hits were further evaluated over a range of 11 concentrations with
both the RapidFire MS assay and an orthogonal fluorescence-based assay.
Further biophysical, biochemical, and cell-based studies of confirmed
hits revealed a WIP1 activator and two inhibitors, one competitive
and one uncompetitive. These new scaffolds are prime candidates for
optimization which might enable inhibitors with improved pharmacokinetics
and a first-in-class WIP1 activator