Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors

Daniel A. Bachovchin, Justin T. Mohr, Anna E. Speers, Chu Wang, Jacob M. Berlin, Timothy P. Spicer, Virneliz Fernandez-Vega, Peter Chase, Peter S. Hodder, Stephan C Schuerer, Daniel K. Nomura, Hugh Rosen, Gregory C. Fu, Benjamin F. Cravatt

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

National Institutes of Health (NIH)-sponsored screening centers provide academic researchers with a special opportunity to pursue small-molecule probes for protein targets that are outside the current interest of, or beyond the standard technologies employed by, the pharmaceutical industry. Here, we describe the outcome of an inhibitor screen for one such target, the enzyme protein phosphatase methylesterase-1 (PME-1), which regulates the methylesterification state of protein phosphatase 2A (PP2A) and is implicated in cancer and neurodegeneration. Inhibitors of PME-1 have not yet been described, which we attribute, at least in part, to a dearth of substrate assays compatible with high-throughput screening. We show that PME-1 is assayable by fluorescence polarization-activity-based protein profiling (fluopol-ABPP) and use this platform to screen the 300,000+ member NIH small-molecule library. This screen identified an unusual class of compounds, the aza-β-lactams (ABLs), as potent (IC50 values of approximately 10 nM), covalent PME-1 inhibitors. Interestingly, ABLs did not derive from a commercial vendor but rather an academic contribution to the public library. We show using competitive-ABPP that ABLs are exquisitely selective for PME-1 in living cells and mice, where enzyme inactivation leads to substantial reductions in demethylated PP2A. In summary, we have combined advanced synthetic and chemoproteomic methods to discover a class of ABL inhibitors that can be used to selectively perturb PME-1 activity in diverse biological systems. More generally, these results illustrate how public screening centers can serve as hubs to create spontaneous collaborative opportunities between synthetic chemistry and chemical biology labs interested in creating first-in-class pharmacological probes for challenging protein targets.

Original languageEnglish
Pages (from-to)6811-6816
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number17
DOIs
StatePublished - Apr 26 2011
Externally publishedYes

Fingerprint

Phosphoric Monoester Hydrolases
Fertilization
Protein Phosphatase 2
National Institutes of Health (U.S.)
Aza Compounds
Small Molecule Libraries
Lactams
Proteins
Fluorescence Polarization
Drug Industry
Enzymes
Inhibitory Concentration 50
Libraries
Research Personnel
Pharmacology
Technology
protein phosphatase methylesterase-1
Neoplasms
protein phosphatase inhibitor-1

ASJC Scopus subject areas

  • General

Cite this

Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors. / Bachovchin, Daniel A.; Mohr, Justin T.; Speers, Anna E.; Wang, Chu; Berlin, Jacob M.; Spicer, Timothy P.; Fernandez-Vega, Virneliz; Chase, Peter; Hodder, Peter S.; Schuerer, Stephan C; Nomura, Daniel K.; Rosen, Hugh; Fu, Gregory C.; Cravatt, Benjamin F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 17, 26.04.2011, p. 6811-6816.

Research output: Contribution to journalArticle

Bachovchin, DA, Mohr, JT, Speers, AE, Wang, C, Berlin, JM, Spicer, TP, Fernandez-Vega, V, Chase, P, Hodder, PS, Schuerer, SC, Nomura, DK, Rosen, H, Fu, GC & Cravatt, BF 2011, 'Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 17, pp. 6811-6816. https://doi.org/10.1073/pnas.1015248108
Bachovchin, Daniel A. ; Mohr, Justin T. ; Speers, Anna E. ; Wang, Chu ; Berlin, Jacob M. ; Spicer, Timothy P. ; Fernandez-Vega, Virneliz ; Chase, Peter ; Hodder, Peter S. ; Schuerer, Stephan C ; Nomura, Daniel K. ; Rosen, Hugh ; Fu, Gregory C. ; Cravatt, Benjamin F. / Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 17. pp. 6811-6816.
@article{189fbd7cb2424702b5bf547c36cc9846,
title = "Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors",
abstract = "National Institutes of Health (NIH)-sponsored screening centers provide academic researchers with a special opportunity to pursue small-molecule probes for protein targets that are outside the current interest of, or beyond the standard technologies employed by, the pharmaceutical industry. Here, we describe the outcome of an inhibitor screen for one such target, the enzyme protein phosphatase methylesterase-1 (PME-1), which regulates the methylesterification state of protein phosphatase 2A (PP2A) and is implicated in cancer and neurodegeneration. Inhibitors of PME-1 have not yet been described, which we attribute, at least in part, to a dearth of substrate assays compatible with high-throughput screening. We show that PME-1 is assayable by fluorescence polarization-activity-based protein profiling (fluopol-ABPP) and use this platform to screen the 300,000+ member NIH small-molecule library. This screen identified an unusual class of compounds, the aza-β-lactams (ABLs), as potent (IC50 values of approximately 10 nM), covalent PME-1 inhibitors. Interestingly, ABLs did not derive from a commercial vendor but rather an academic contribution to the public library. We show using competitive-ABPP that ABLs are exquisitely selective for PME-1 in living cells and mice, where enzyme inactivation leads to substantial reductions in demethylated PP2A. In summary, we have combined advanced synthetic and chemoproteomic methods to discover a class of ABL inhibitors that can be used to selectively perturb PME-1 activity in diverse biological systems. More generally, these results illustrate how public screening centers can serve as hubs to create spontaneous collaborative opportunities between synthetic chemistry and chemical biology labs interested in creating first-in-class pharmacological probes for challenging protein targets.",
author = "Bachovchin, {Daniel A.} and Mohr, {Justin T.} and Speers, {Anna E.} and Chu Wang and Berlin, {Jacob M.} and Spicer, {Timothy P.} and Virneliz Fernandez-Vega and Peter Chase and Hodder, {Peter S.} and Schuerer, {Stephan C} and Nomura, {Daniel K.} and Hugh Rosen and Fu, {Gregory C.} and Cravatt, {Benjamin F.}",
year = "2011",
month = "4",
day = "26",
doi = "10.1073/pnas.1015248108",
language = "English",
volume = "108",
pages = "6811--6816",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "17",

}

TY - JOUR

T1 - Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors

AU - Bachovchin, Daniel A.

AU - Mohr, Justin T.

AU - Speers, Anna E.

AU - Wang, Chu

AU - Berlin, Jacob M.

AU - Spicer, Timothy P.

AU - Fernandez-Vega, Virneliz

AU - Chase, Peter

AU - Hodder, Peter S.

AU - Schuerer, Stephan C

AU - Nomura, Daniel K.

AU - Rosen, Hugh

AU - Fu, Gregory C.

AU - Cravatt, Benjamin F.

PY - 2011/4/26

Y1 - 2011/4/26

N2 - National Institutes of Health (NIH)-sponsored screening centers provide academic researchers with a special opportunity to pursue small-molecule probes for protein targets that are outside the current interest of, or beyond the standard technologies employed by, the pharmaceutical industry. Here, we describe the outcome of an inhibitor screen for one such target, the enzyme protein phosphatase methylesterase-1 (PME-1), which regulates the methylesterification state of protein phosphatase 2A (PP2A) and is implicated in cancer and neurodegeneration. Inhibitors of PME-1 have not yet been described, which we attribute, at least in part, to a dearth of substrate assays compatible with high-throughput screening. We show that PME-1 is assayable by fluorescence polarization-activity-based protein profiling (fluopol-ABPP) and use this platform to screen the 300,000+ member NIH small-molecule library. This screen identified an unusual class of compounds, the aza-β-lactams (ABLs), as potent (IC50 values of approximately 10 nM), covalent PME-1 inhibitors. Interestingly, ABLs did not derive from a commercial vendor but rather an academic contribution to the public library. We show using competitive-ABPP that ABLs are exquisitely selective for PME-1 in living cells and mice, where enzyme inactivation leads to substantial reductions in demethylated PP2A. In summary, we have combined advanced synthetic and chemoproteomic methods to discover a class of ABL inhibitors that can be used to selectively perturb PME-1 activity in diverse biological systems. More generally, these results illustrate how public screening centers can serve as hubs to create spontaneous collaborative opportunities between synthetic chemistry and chemical biology labs interested in creating first-in-class pharmacological probes for challenging protein targets.

AB - National Institutes of Health (NIH)-sponsored screening centers provide academic researchers with a special opportunity to pursue small-molecule probes for protein targets that are outside the current interest of, or beyond the standard technologies employed by, the pharmaceutical industry. Here, we describe the outcome of an inhibitor screen for one such target, the enzyme protein phosphatase methylesterase-1 (PME-1), which regulates the methylesterification state of protein phosphatase 2A (PP2A) and is implicated in cancer and neurodegeneration. Inhibitors of PME-1 have not yet been described, which we attribute, at least in part, to a dearth of substrate assays compatible with high-throughput screening. We show that PME-1 is assayable by fluorescence polarization-activity-based protein profiling (fluopol-ABPP) and use this platform to screen the 300,000+ member NIH small-molecule library. This screen identified an unusual class of compounds, the aza-β-lactams (ABLs), as potent (IC50 values of approximately 10 nM), covalent PME-1 inhibitors. Interestingly, ABLs did not derive from a commercial vendor but rather an academic contribution to the public library. We show using competitive-ABPP that ABLs are exquisitely selective for PME-1 in living cells and mice, where enzyme inactivation leads to substantial reductions in demethylated PP2A. In summary, we have combined advanced synthetic and chemoproteomic methods to discover a class of ABL inhibitors that can be used to selectively perturb PME-1 activity in diverse biological systems. More generally, these results illustrate how public screening centers can serve as hubs to create spontaneous collaborative opportunities between synthetic chemistry and chemical biology labs interested in creating first-in-class pharmacological probes for challenging protein targets.

UR - http://www.scopus.com/inward/record.url?scp=79955554526&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955554526&partnerID=8YFLogxK

U2 - 10.1073/pnas.1015248108

DO - 10.1073/pnas.1015248108

M3 - Article

C2 - 21398589

AN - SCOPUS:79955554526

VL - 108

SP - 6811

EP - 6816

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 17

ER -