A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate (original) (raw)

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In the version of this article initially published, the author omitted some funding sources: NIH (R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389 to D.M.S.) and the US Department of Defense (W81XWH-14-PRCRP-IA to D.M.S.). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank T. Wang and E. Edenberg for critical reading of the manuscript, S. Murphy for assistance with mouse experiments, and J. Pacold of the Lawrence Berkeley National Laboratory for assistance in interpreting _T_m data. This research is supported by the Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation (DRG-112-12), a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship (BC120208), and an ASTRO Resident Seed Grant (RA-2011-1) (all to M.E.P.)., by Susan G. Komen for the Cure (grant to R.L.P.), by an EMBO Long-Term Fellowship (to M.A.-R.), by the NIH (R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389 to D.M.S.), by the US Department of Defense (W81XWH-14-PRCRP-IA to D.M.S.) and by the Stewart Trust (to D.M.S.). D.M.S. is an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
    Michael E Pacold, Sze Ham Chan, Lotteke J Y M Swier, Walter W Chen, Steve Cho, Elizaveta Freinkman, Monther Abu-Remaileh, Chieh Min Liu, Minerva Zhou, Min Jung Koh, Haeyoon Chung & David M Sabatini
  2. Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    Michael E Pacold, Sze Ham Chan, Lotteke J Y M Swier, Walter W Chen, Steve Cho, Monther Abu-Remaileh, Chieh Min Liu, Minerva Zhou, Min Jung Koh, Haeyoon Chung & David M Sabatini
  3. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA
    Michael E Pacold, Sze Ham Chan, Caroline A Lewis, Lotteke J Y M Swier, Walter W Chen, Lucas B Sullivan, Brian P Fiske, Steve Cho, Monther Abu-Remaileh, Chieh Min Liu, Minerva Zhou, Min Jung Koh, Haeyoon Chung, Shawn M Davidson, Alba Luengo, Matthew G Vander Heiden & David M Sabatini
  4. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    Michael E Pacold, Sze Ham Chan, Lotteke J Y M Swier, Walter W Chen, Steve Cho, Monther Abu-Remaileh, Chieh Min Liu, Minerva Zhou, Min Jung Koh, Haeyoon Chung & David M Sabatini
  5. Dana-Farber Cancer Institute, Longwood Center, Boston, Massachusetts, USA
    Michael E Pacold & Nathanael S Gray
  6. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
    Michael E Pacold & Sze Ham Chan
  7. National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA
    Kyle R Brimacombe, Jason M Rohde, Amy Q Wang, Xin Xu, Adam Yasgar, Li Liu, Ganesha Rai, Min Shen & Matthew B Boxer
  8. New York University Langone Medical Center, New York, New York, USA.,
    Richard Possemato
  9. Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA
    Kıvanç Birsoy
  10. Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel–Canada, The Hebrew University–Hadassah Medical School, Jerusalem, Israel
    Yoav D Shaul
  11. University of Texas Southwestern Medical Center, Dallas, Texas, USA.
    Kenneth D Westover

Authors

  1. Michael E Pacold
  2. Kyle R Brimacombe
  3. Sze Ham Chan
  4. Jason M Rohde
  5. Caroline A Lewis
  6. Lotteke J Y M Swier
  7. Richard Possemato
  8. Walter W Chen
  9. Lucas B Sullivan
  10. Brian P Fiske
  11. Steve Cho
  12. Elizaveta Freinkman
  13. Kıvanç Birsoy
  14. Monther Abu-Remaileh
  15. Yoav D Shaul
  16. Chieh Min Liu
  17. Minerva Zhou
  18. Min Jung Koh
  19. Haeyoon Chung
  20. Shawn M Davidson
  21. Alba Luengo
  22. Amy Q Wang
  23. Xin Xu
  24. Adam Yasgar
  25. Li Liu
  26. Ganesha Rai
  27. Kenneth D Westover
  28. Matthew G Vander Heiden
  29. Min Shen
  30. Nathanael S Gray
  31. Matthew B Boxer
  32. David M Sabatini

Contributions

M.E.P. and D.M.S. conceived of the study and designed most of the experiments with advice from N.S.G. M.E.P. performed most of the experiments (in vitro assays, cell viability and proliferation, western blots, xenografts, knockdowns, and metabolomics) with assistance from L.J.Y.M.S., S.H.C., R.P., S.W.C., M.Z., E.F., K.B., M.A.-R., Y.D.S., C.M.L., H.C., M.J.K., W.W.C., and K.D.W. and in discussion with C.A.L., B.P.F., L.B.S. and M.G.V.H., K.R.B. and M.B.B. helped design and carried out the quantitative high-throughput screen. J.M.R., L.L., G.R., and M.B.B. designed and carried out structure–activity relationship (SAR) analysis and synthesis of all compounds. A.Y. assisted with additional in vitro assays, and A.Q.W. and X.X. designed and carried out pharmacokinetic analyses. M.S. was responsible for chemoinformatics during the screen and for SAR. S.M.D., A.L., and M.G.V.H. designed and carried out in vivo isotope tracing experiments. M.E.P. and D.M.S. wrote and all authors edited the manuscript.

Corresponding author

Correspondence toDavid M Sabatini.

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Competing interests

D.M.S. is a founder and holds equity in Raze Therapeutics, which has interest in targeting one-carbon metabolism in cancer. M.E.P. is a consultant to and holds equity in Raze Therapeutics.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–9. (PDF 12061 kb)

Supplementary Note

Synthetic Procedures (PDF 173 kb)

Supplementary Data Set 1

Selectivity profile of NCT-502, NCT-503 and inactive compound. The activity of NCT-502, NCT-503 and the inactive compound was tested against a panel of 168 GPCR candidates. (XLSX 429 kb)

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Pacold, M., Brimacombe, K., Chan, S. et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.Nat Chem Biol 12, 452–458 (2016). https://doi.org/10.1038/nchembio.2070

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