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

Bachovchin, Daniel A. and Mohr, Justin T. and Speers, Anna E. and Wang, Chu and Berlin, Jacob M. and Spicer, Timothy P. and Fernandez-Vega, Virneliz and Chase, Peter and Hodder, Peter S. and Schürer, Stephan C. and Nomura, Daniel K. and Rosen, Hugh and Fu, Gregory C. and Cravatt, Benjamin F. (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, 108 (17). pp. 6811-6816. ISSN 0027-8424. PMCID PMC3084096. doi:10.1073/pnas.1015248108.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription Information CentralArticle
Mohr, Justin T.0000-0002-7005-3322
Berlin, Jacob M.0000-0001-7498-766X
Fu, Gregory C.0000-0002-0927-680X
Additional Information:© 2011 National Academy of Sciences. Edited by Stuart L. Schreiber, Broad Institute, Cambridge, MA, and approved January 13, 2011 (received for review November 24, 2010). We thank Tianyang Ji, David Milliken, Kim Masuda, Benjamin Kipper, and Jaclyn M. Murphy for technical assistance. This work was supported by National Institutes of Health grants CA132630 (B.F.C.), MH084512 (H.R.), GM57034 (G.C.F.), and GM086040 (postdoctoral fellowship to J.T.M.); the National Science Foundation (predoctoral fellowship to D.A.B.); the California Breast Cancer Research Program (predoctoral fellowship to D.A.B.); and The Skaggs Institute for Chemical Biology. Author contributions: D.A.B., J.T.M., H.R., G.C.F., and B.F.C. designed research; D.A.B., J.T.M., J.M.B., T.P.S., V.F.-V., P.C., P.S.H., S.C.S., and D.K.N. performed research; D.A.B., J.T.M., C.W., J.M.B., and S.C.S. contributed new reagents/analytic tools; D.A.B., J.T.M., A.E.S., C.W., T.P.S., P.S.H., S.C.S., H.R., G.C.F., and B.F.C. analyzed data; and D.A.B., J.T.M., A.E.S., H.R., G.C.F., and B.F.C. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at
Funding AgencyGrant Number
NIH Postdoctoral FellowshipGM086040
NSF Graduate Research FellowshipUNSPECIFIED
California Breast Cancer Research ProgramUNSPECIFIED
Skaggs Institute for Chemical BiologyUNSPECIFIED
Issue or Number:17
PubMed Central ID:PMC3084096
Record Number:CaltechAUTHORS:20200507-105436538
Persistent URL:
Official Citation: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. Schürer, Daniel K. Nomura, Hugh Rosen, Gregory C. Fu, Benjamin F. Cravatt. Proceedings of the National Academy of Sciences Apr 2011, 108 (17) 6811-6816; DOI: 10.1073/pnas.1015248108
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103068
Deposited By: Tony Diaz
Deposited On:07 May 2020 21:16
Last Modified:16 Nov 2021 18:18

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