Rational design of selective allosteric inhibitors of PHGDH and serine synthesis with anti-tumor activity
Open accessAbstract
Metabolic reprogramming in cancer cells facilitates growth and proliferation. Increased activity of the serine biosynthetic pathway through the enzyme phosphoglycerate dehydrogenase (PHGDH) contributes to tumorigenesis. With a small substrate and a weak binding cofactor, (NAD+), inhibitor development for PHGDH remains challenging. Instead of targeting the PHGDH active site, we computationally identified two potential allosteric sites and virtually screened compounds that can bind to these sites. With subsequent characterization, we successfully identified PHGDH non-NAD+-competing allosteric inhibitors that attenuate its enzyme activity, selectively inhibit de novo serine synthesis in cancer cells, and reduce tumor growth in vivo. Our study not only identifies novel allosteric inhibitors for PHGDH to probe its function and potential as a therapeutic target, but also provides a general strategy for the rational design of small-molecule modulators of metabolic enzyme function.
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Small-molecule inhibitors targeting PHGDH inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models.
“and small-molecule inhibitors targeting PHGDH have been shown to inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models (Mullarky et al., 2016; Pacold et al., 2016; Wang et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Wang et al., 2017
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Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425 · see citing works
Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., Repasky, M. P., Knoll, E. H., Shelley, M., Perry, J. K., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm0306430 · Cited by 10,057 · see citing works
RNA-Guided Human Genome Engineering via Cas9
Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., Norville, J. E., & Church, G. M. (2013) · Science · doi:10.1126/science.1232033 · Cited by 9,210 · see citing works
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · cited 1× · see citing works
“…malignant transformation also involve numerous other pathway alterations such as the increased flux of the pentose phosphate pathway, elevated rates of lipid biosynthesis, high glutamine consumption, maintenance of redox homeostasis, and alterations in autophagy Cell C (Pavlova and Thompson, 2016).”
Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., & Banks, J. L. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030644s · Cited by 5,280 · see citing works
Genome-scale CRISPR-Cas9 knockout screening in human cells
Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., et al. (2014) · Science · doi:10.1126/science.1247005 · Cited by 5,234 · see citing works
Chou, T.-C. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.3.10 · Cited by 5,163 · see citing works
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017 · see citing works
Baell, J. B., & Holloway, G. A. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm901137j · Cited by 3,963 · see citing works
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683 · see citing works
Serine, glycine and one-carbon units: cancer metabolism in full circle
Locasale, J. W. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3557 · Cited by 1,669 · see citing works
Self-citationTargeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice
Sonveaux, P., Végran, F., Schroeder, T., Wergin, M., Verrax, J., Rabbani, Z. N., Saedeleer, C. J. D., Kennedy, K. M., Diepart, C., Jordan, B. F., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36843 · Cited by 1,635 · see citing works
Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., et al. (2011) · Nature Genetics · doi:10.1038/ng.890 · Cited by 1,120 · see citing works
Self-citationQuantitative flux analysis reveals folate-dependent NADPH production
Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D. (2014) · Nature · doi:10.1038/nature13236 · Cited by 1,114 · see citing works
A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening
McGovern, S. L., Caselli, E., Grigorieff, N., & Shoichet, B. K. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm010533y · Cited by 1,048 · see citing works
E-CRISP: fast CRISPR target site identification
Heigwer, F., Kerr, G., & Boutros, M. (2014) · Nature Methods · doi:10.1038/nmeth.2812 · Cited by 866 · see citing works
NRF2 regulates serine biosynthesis in non–small cell lung cancer
DeNicola, G. M., Chen, P.-H., Mullarky, E., Sudderth, J., Hu, Z., Wu, D., Tang, H., Xie, Y., Asara, J. M., Huffman, K. E., et al. (2015) · Nature Genetics · doi:10.1038/ng.3421 · Cited by 747 · see citing works
Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism
Mentch, S. J., Mehrmohamadi, M., Huang, L., Liu, X., Gupta, D., Mattocks, D. A. L., Padilla, P. G., Ables, G. P., Bamman, M. M., Thalacker‐Mercer, A. E., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.08.024 · Cited by 706 · see citing works
Self-citationMetabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 705 · see citing works
A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
Pacold, M. E., Brimacombe, K. R., Chan, S. H., Rohde, J. M., Lewis, C. A., Swier, L. J. Y. M., Possemato, R., Chen, W. W., Sullivan, L. B., Fiske, B. P., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2070 · Cited by 553 · see citing works
Mullarky, E., Lucki, N. C., Beheshti Zavareh, R., Anglin, J. L., Gomes, A. P., Nicolay, B. N., Wong, J. C. Y., Christen, S., Takahashi, H., Singh, P. K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521548113 · Cited by 333 · see citing works
Ding, J., Li, T., Wang, X., Zhao, E., Choi, J.-H., Yang, L., Zha, Y., Dong, Z., Huang, S., Asara, J. M., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.004 · Cited by 244 · see citing works
Emerging Computational Methods for the Rational Discovery of Allosteric Drugs
Wagner, J., Lee, C. T., Durrant, J. D., Malmstrom, R. D., Feher, V. A., & Amaro, R. E. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00631 · Cited by 230 · see citing works
MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors
Birsoy, K., Wang, T., Possemato, R., Yilmaz, Ö. H., Koch, C. E., Chen, W. W., Hutchins, A., Gültekin, Y., Peterson, T. R., Carette, J. E., et al. (2012) · Nature Genetics · doi:10.1038/ng.2471 · Cited by 226 · see citing works
Control of Nutrient Stress-Induced Metabolic Reprogramming by PKCζ in Tumorigenesis
Ma, L., Tao, Y., Durán, Á., Lladó, V., Galvez, A. S., Barger, J. F., Castilla, E. A., Chen, J., Yajima, T., Porollo, A., et al. (2013) · Cell · doi:10.1016/j.cell.2012.12.028 · Cited by 204 · see citing works
Yuan, Y., Pei, J., & Lai, L. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319120019 · Cited by 199 · see citing works
Self-citationLigBuilder 2: A Practical de Novo Drug Design Approach
Yuan, Y., Pei, J., & Lai, L. (2011) · Journal of Chemical Information and Modeling · doi:10.1021/ci100350u · Cited by 199 · see citing works
Self-citationAllostery and population shift in drug discovery
Kar, G., Keskin, Ö., Gürsoy, A., & Nussinov, R. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2010.09.002 · Cited by 190 · see citing works
Characterization of Chemical Libraries for Luciferase Inhibitory Activity
Auld, D. S., Southall, N. T., Jadhav, A., Johnson, R. L., Diller, D., Simeonov, A. M., Austin, C. P., & Inglese, J. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701302v · Cited by 183 · see citing works
Development and Quantitative Evaluation of a High-Resolution Metabolomics Technology
Liu, X., Ser, Z., & Locasale, J. W. (2014) · Analytical Chemistry · doi:10.1021/ac403845u · Cited by 174 · see citing works
Self-citationKDM4C and ATF4 Cooperate in Transcriptional Control of Amino Acid Metabolism
Zhao, E., Ding, J., Xia, Y., Liu, M., Ye, B., Choi, J.-H., Yan, C., Dong, Z., Huang, S., Zha, Y., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.053 · Cited by 162 · see citing works
Ou, Y., Wang, S.-J., Jiang, L., Zheng, B., & Gu, W. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.616359 · Cited by 154 · see citing works
Yamada, K., Hara, N., Shibata, T., Osago, H., & Tsuchiya, M. (2006) · Analytical Biochemistry · doi:10.1016/j.ab.2006.02.017 · Cited by 154 · see citing works
Phosphoserine Aminotransferase Deficiency: A Novel Disorder of the Serine Biosynthesis Pathway
Hart, C., Race, V., Achouri, Y., Wiame, E., Sharrard, M. J., Olpin, S. E., Watkinson, J., Bonham, J. R., Jaeken, J., Matthijs, G., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/517888 · Cited by 120 · see citing works
Unraveling structural mechanisms of allosteric drug action
Nussinov, R., & Tsai, C.-J. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.03.006 · Cited by 119 · see citing works
Ainscough, E. W., Brodie, A. M., Denny, W. A., Finlay, G. J., Gothe, S. A., & Ranford, J. D. (1999) · Journal of Inorganic Biochemistry · doi:10.1016/s0162-0134(99)00131-2 · Cited by 95 · see citing works
Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth
Chen, J., Chung, F., Yang, G., Pu, M., Gao, H., Jiang, W., Yin, H., Capka, V., Kasibhatla, S., Laffitte, B., et al. (2013) · Oncotarget · doi:10.18632/oncotarget.1540 · Cited by 82 · see citing works
Motions of Allosteric and Orthosteric Ligand-Binding Sites in Proteins are Highly Correlated
Ma, X., Meng, H., & Lai, L. (2016) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.6b00039 · Cited by 81 · see citing works
Self-citationSystems Biology Brings New Dimensions for Structure-Based Drug Design
Pei, J., Yin, N., Ma, X., & Lai, L. (2014) · Journal of the American Chemical Society · doi:10.1021/ja504810z · Cited by 74 · see citing works
Self-citationClem, B. F., Clem, A. L., Yalçın, A., Goswami, U., Arumugam, S., Telang, S., Trent, J. O., & Chesney, J. A. (2011) · Oncogene · doi:10.1038/onc.2011.51 · Cited by 69 · see citing works
Yang, Q., Yang, Y., Li, L., Sun, W. Y., Zhu, X. D., & Huang, Y. (2015) · ACS Applied Materials & Interfaces · doi:10.1021/am509204u · Cited by 61 · see citing works
Meng, H., McClendon, C. L., Dai, Z., Li, K., Zhang, X., He, S., Shang, E., Liu, Y., & Lai, L. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01011 · Cited by 50 · see citing works
Self-citationDiversity of Allosteric Regulation in Proteases
Merdanovic, M., Mönig, T., Ehrmann, M., & Kaiser, M. (2012) · ACS Chemical Biology · doi:10.1021/cb3005935 · Cited by 49 · see citing works
Qi, Y., Wang, Q., Tang, B., & Lai, L. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300395h · Cited by 49 · see citing works
Self-citationUnterlass, J. E., Baslé, A., Blackburn, T. J., Tucker, J. A., Cano, C., Noble, M. E. M., & Curtin, N. J. (2016) · Oncotarget · doi:10.18632/oncotarget.11487 · Cited by 42 · see citing works
Botham, R. C., Fan, T. M., Im, I., Borst, L. B., Dirikolu, L., & Hergenrother, P. J. (2014) · Journal of the American Chemical Society · doi:10.1021/ja4124303 · Cited by 40 · see citing works
Wang, Q., Qi, Y., Yin, N., & Lai, L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094829 · Cited by 29 · see citing works
Self-citationCrystal structure of human 3-phosphoglycerate dehydrogenase
Turnbull, A. P., Salah, E., Savitsky, P. A., Gileadi, O., von Delft, F., Edwards, A. M., Arrowsmith, C. H., Weigelt, J., Sundström, M., & Oppermann, U. C. T. (2006) · Worldwide Protein Data Bank · doi:10.2210/pdb2g76/pdb · Cited by 4 · see citing works
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Stine, Z. E., Schug, Z. T., Salvino, J. M., & Dang, C. V. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00339-6 · Cited by 1,189 · see citing works
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Lieu, E. L., Nguyen, T. A., Rhyne, S., & Kim, J. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0375-3 · Cited by 827 · see citing works
Metabolomics in cancer research and emerging applications in clinical oncology
Schmidt, D. R., Patel, R., Kirsch, D. G., Lewis, C. A., Heiden, M. G. V., & Locasale, J. W. (2021) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21670 · Cited by 652 · see citing works
Self-citationMetabolic modeling of single Th17 cells reveals regulators of autoimmunity
Wagner, A., Wang, C., Fessler, J., DeTomaso, D., Avila-Pacheco, J., Kaminski, J., Zaghouani, S., Christian, E., Thakore, P., Schellhaass, B., et al. (2021) · Cell · doi:10.1016/j.cell.2021.05.045 · Cited by 524 · see citing works
Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect
Sun, L., Suo, C., Li, S., Zhang, H., & Gao, P. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.06.005 · Cited by 366 · see citing works
Ducker, G. S., Ghergurovich, J. M., Mainolfi, N., Suri, V., Jeong, S. K., Hsin-Jung Li, S., Friedman, A., Manfredi, M. G., Gitai, Z., Kim, H., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1706617114 · Cited by 261 · see citing works
The ins and outs of serine and glycine metabolism in cancer
Geeraerts, S. L., Heylen, E., Keersmaecker, K. D., & Kampen, K. R. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00329-9 · Cited by 250 · see citing works
Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function
Kurniawan, H., Franchina, D. G., Guerra, L., Bonetti, L., Soriano‐Baguet, L., Grusdat, M., Schlicker, L., Hunewald, O. E., Dostert, C., Merz, M. P., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.03.004 · Cited by 245 · see citing works
Reid, M. A., Allen, A. E., Liu, S., Liberti, M. V., Liu, P., Liu, X., Dai, Z., Gao, X., Wang, Q., Liu, Y., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07868-6 · Cited by 228 · see citing works
Self-citationThe Diverse Functions of Non-Essential Amino Acids in Cancer
Choi, B.-H., & Coloff, J. L. (2019) · Cancers · doi:10.3390/cancers11050675 · Cited by 213 · see citing works
Serine and Functional Metabolites in Cancer
Newman, A. C., & Maddocks, O. D. K. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.05.001 · Cited by 168 · see citing works
Serine metabolism orchestrates macrophage polarization by regulating the IGF1–p38 axis
Shan, X., Hu, P., Ni, L., Shen, L., Zhang, Y., Ji, Z., Cui, Y., Guo, M., Wang, H., Ran, L., et al. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-022-00925-7 · Cited by 167 · see citing works
Glucose Metabolism and Glucose Transporters in Breast Cancer
Shin, E., & Koo, J. S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.728759 · Cited by 169 · see citing works
Zhang, D., Li, A. M., Hu, G., Huang, M., Yang, F., Zhang, L., Wellen, K. E., Xu, X., Conn, C. S., Zou, W., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.01.010 · Cited by 141 · see citing works
Wang, K., Luo, L., Fu, S., Wang, M., Wang, Z., Dong, L., Wu, X., Dai, L., Peng, Y., Shen, G., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36708-5 · Cited by 133 · see citing works
The complexity of the serine glycine one-carbon pathway in cancer
Reina‐Campos, M., Díaz-Meco, M. T., & Moscat, J. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201907022 · Cited by 123 · see citing works
Dong, J.-K., Lei, H.-M., Liang, Q., Tang, Y., Zhou, Y., Wang, Y., Zhang, S., Li, W., Tong, Y., Zhuang, G., et al. (2018) · Theranostics · doi:10.7150/thno.23177 · Cited by 103 · see citing works
Liu, J., Zhang, C., Wu, H., Sun, X., Li, Y., HUANG, S. H., Yue, X., Lu, S., Shen, Z., Su, X., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci132876 · Cited by 98 · see citing works
Serine synthesis sustains macrophage IL-1β production via NAD+-dependent protein acetylation
Wang, C., Chen, Q., Chen, S., Fan, L., Gan, Z., Zhao, M., Shi, L., Bin, P., Yang, G., Zhou, X., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.01.002 · Cited by 97 · see citing works
The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer
Zhao, X., Fu, J., Du, J., & Xu, W. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.41051 · Cited by 90 · see citing works
Cai, Z.-N., Li, W., Hager, S., Wilson, J. L., Afjehi-Sadat, L., Heiss, E. H., Weichhart, T., Heffeter, P., & Weckwerth, W. (2024) · Cellular & Molecular Immunology · doi:10.1038/s41423-024-01134-0 · Cited by 89 · see citing works
L-serine synthesis via the phosphorylated pathway in humans
Murtas, G., Marcone, G. L., Sacchi, S., & Pollegioni, L. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03574-z · Cited by 87 · see citing works
D-3-Phosphoglycerate Dehydrogenase
Grant, G. A. (2018) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2018.00110 · Cited by 82 · see citing works
PHGDH: a novel therapeutic target in cancer
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Zhu, H., Zhang, Y., Li, W., & Huang, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415961 · Cited by 80 · see citing works
Weinstabl, H., Treu, M., Rinnenthal, J., Zahn, S. K., Ettmayer, P., Bader, G., Dahmann, G., Kessler, D., Rumpel, K., Mischerikow, N., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00718 · Cited by 79 · see citing works
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Signaling Pathways Regulating Redox Balance in Cancer Metabolism
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The PHGDH enigma: Do cancer cells only need serine or also a redox modulator?
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Bioprospecting of microbial enzymes: current trends in industry and healthcare
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Rathore, R., Caldwell, K. E., Schutt, C. R., Brashears, C. B., Prudner, B. C., Ehrhardt, W. R., Leung, C. H., Lin, H. Y., Daw, N. C., Beird, H. C., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108678 · Cited by 51 · see citing works
3-Phosphoglycerate dehydrogenase: a potential target for cancer treatment
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Biosynthesis and biotechnological application of non-canonical amino acids: Complex and unclear
Zou, H., Li, L., Zhang, T., Shi, M., Zhang, N., Huang, J., & Xian, M. (2018) · Biotechnology Advances · doi:10.1016/j.biotechadv.2018.07.008 · Cited by 50 · see citing works
Zhang, Y., Liu, Z., Wang, X., Jian, H., Xiao, H., & Wen, T. (2022) · Cancer Gene Therapy · doi:10.1038/s41417-022-00470-5 · Cited by 47 · see citing works
Kiweler, N., Delbrouck, C., Pozdeev, V. I., Neises, L., Soriano‐Baguet, L., Eiden, K., Xian, F., Benzarti, M., Haase, L., Koncina, E., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30363-y · Cited by 45 · see citing works
Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH
Zheng, M., Guo, J., Xu, J., Yang, K., Tang, R., Gu, X., Li, H., & Chen, L. (2019) · Food & Function · doi:10.1039/c9fo00394k · Cited by 47 · see citing works
MYCN and Metabolic Reprogramming in Neuroblastoma
Bansal, M., Gupta, A., & Ding, H. (2022) · Cancers · doi:10.3390/cancers14174113 · Cited by 46 · see citing works
Rohde, J. M., Brimacombe, K. R., Liu, L., Pacold, M. E., Yasgar, A., Cheff, D. M., Lee, T. D., Rai, G., Baljinnyam, B., Li, Z., et al. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.02.016 · Cited by 46 · see citing works
PHGDH as a mechanism for resistance in metabolically-driven cancers
Rathore, R., Schutt, C. R., & Tine, B. A. V. (2020) · Cancer Drug Resistance · doi:10.20517/cdr.2020.46 · Cited by 46 · see citing works
Allostery of multidomain proteins with disordered linkers
Huang, Q., Li, M., Lai, L., & Liu, Z. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.01.017 · Cited by 42 · see citing works
Self-citationE-Cadherin Induces Serine Synthesis to Support Progression and Metastasis of Breast Cancer
Lee, G., Wong, C., Cho, A., West, J. J., Crawford, A. J., Russo, G. C., Si, B. R., Kim, J.-W., Hoffner, L. A., Jang, C., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-3082 · Cited by 46 · see citing works
Targeting allosteric regulation of cancer metabolism
Kremer, D. M., & Lyssiotis, C. A. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-00997-6 · Cited by 40 · see citing works
Shu, Y., Hao, Y., Feng, J., Liu, H., Li, S., Feng, J., Jiang, Z., Ye, L., Zhou, Y., Sun, Y., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2022111550 · Cited by 39 · see citing works
Applications of oxetanes in drug discovery and medicinal chemistry
Huang, G., Hucek, D. G., Cierpicki, T., & Grembecka, J. E. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115802 · Cited by 40 · see citing works
The advancements and prospective developments in anti-tumor targeted therapy
Leng, G., Duan, B., Liu, J., Song, L., Zhao, W., Wang, S., Hou, G., & Qu, J. (2024) · Neoplasia · doi:10.1016/j.neo.2024.101024 · Cited by 41 · see citing works
Choi, B.-H., Rawat, V., Hogstrom, J. M., Burns, P. A., Conger, K. O., Özgürses, M. E., Patel, J. M., Mehta, T. S., Warren, A., Selfors, L. M., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110278 · Cited by 36 · see citing works
Target enzymes in serine‐glycine‐one‐carbon metabolic pathway for cancer therapy
Sun, W. Y., Zhao, E., & Cui, H. (2022) · International Journal of Cancer · doi:10.1002/ijc.34353 · Cited by 39 · see citing works
PHGDH supports liver ceramide synthesis and sustains lipid homeostasis
Kang, Y. P., Falzone, A., Liu, M., González‐Sánchez, P., Choi, B.-H., Coloff, J. L., Saller, J. J., Karreth, F. A., & DeNicola, G. M. (2020) · Cancer & Metabolism · doi:10.1186/s40170-020-00212-x · Cited by 32 · see citing works
A d-2-hydroxyglutarate biosensor based on specific transcriptional regulator DhdR
Xiao, D., Zhang, W., Guo, X., Liu, Y., Hu, C., Guo, S., Kang, Z., Xu, X., Ma, C., Gao, C., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27357-7 · Cited by 34 · see citing works
Self-citationAzacoccone E inhibits cancer cell growth by targeting 3-phosphoglycerate dehydrogenase
Guo, J., Gu, X., Zheng, M., Zhang, Y., Chen, L., & Li, H. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.02.037 · Cited by 35 · see citing works
Adapalene inhibits ovarian cancer ES-2 cells growth by targeting glutamic-oxaloacetic transaminase 1
Wang, Q., Zhang, Q., Luan, S., Yang, K., Zheng, M., Li, K., Chen, L., & Li, H. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103315 · Cited by 34 · see citing works
Self-citationWarburg and Krebs and related effects in cancer
Unterlass, J. E., & Curtin, N. J. (2019) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2019.4 · Cited by 35 · see citing works
Issaq, S. H., Mendoza, A., Kidner, R. Q., Rosales, T. I., Duveau, D. Y., Heske, C. M., Rohde, J. M., Boxer, M. B., Thomas, C. J., DeBerardinis, R. J., et al. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0748 · Cited by 33 · see citing works
Phosphoglycerate dehydrogenase (PHGDH) inhibitors: a comprehensive review 2015–2020
Spillier, Q., & Frédérick, R. (2021) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2021.1890028 · Cited by 32 · see citing works
Protein topology and allostery
Xie, J., & Lai, L. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.01.011 · Cited by 31 · see citing works
Self-citationUncovering the Dominant Motion Modes of Allosteric Regulation Improves Allosteric Site Prediction
Xie, J., Wang, S., Xu, Y., Deng, M., & Lai, L. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c01267 · Cited by 31 · see citing works
Self-citationAmino acid metabolism in breast cancer: pathogenic drivers and therapeutic opportunities
Liu, Y., Zong, X., Altea‐Manzano, P., & Fu, J. (2025) · Protein & Cell · doi:10.1093/procel/pwaf011 · Cited by 30 · see citing works
Self-citationThe role of serine metabolism in lung cancer: From oncogenesis to tumor treatment
Zhou, X., Tian, C., Cao, Y., Zhao, M., & Wang, K. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.1084609 · Cited by 30 · see citing works
Luo, W., Zou, Z., Nie, Y., Luo, J., Ming, Z., Hu, X., Luo, T., Ouyang, M., Mingquan, L., Tang, H., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06672-z · Cited by 28 · see citing works
Targeting the Serine Pathway: A Promising Approach against Tuberculosis?
Haufroid, M., & Wouters, J. (2019) · Pharmaceuticals · doi:10.3390/ph12020066 · Cited by 28 · see citing works
Spillier, Q., Ravez, S., Unterlass, J. E., Corbet, C., Degavre, C., Féron, O., & Frédérick, R. (2020) · Pharmaceuticals · doi:10.3390/ph13020020 · Cited by 27 · see citing works
Arlt, B., Zasada, C., Baum, K., Wünschel, J., Mastrobuoni, G., Lodrini, M., Astrahantseff, K., Winkler, A., Schulte, J. H., Finkler, S., et al. (2020) · International Journal of Cancer · doi:10.1002/ijc.33423 · Cited by 25 · see citing works
Dai, Z., Xu, L., Xu, L., Liao, K., Deng, S., Chen, Q., Wang, Q., Wang, Q., Gao, S., Li, B., et al. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0439-y · Cited by 25 · see citing works
Self-citationPivotal role of exogenous pyruvate in human natural killer cell metabolism
Coquillat, N. K., Picq, L., Hamond, A., Megy, P., Benezech, S., Drouillard, A., Lager-Lachaud, N., Cahoreau, E., Moreau, M., Fallone, L., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-024-01188-4 · Cited by 24 · see citing works
Allosteric Type and Pathways Are Governed by the Forces of Protein–Ligand Binding
Huang, Q., Song, P., Chen, Y., Liu, Z., & Lai, L. (2021) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.1c01253 · Cited by 24 · see citing works
Self-citationBiophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors
Tan, Y., Zhou, X., Gong, Y., Gou, K., Luo, Y., Jia, D., Dai, L., Zhao, Y., & Sun, Q. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04022-2 · Cited by 23 · see citing works
Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy
Gao, D., Tang, S., Cen, Y., Yuan, L., Lan, X., Li, Q., Lin, G., Huang, M., & Tian, P. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01202 · Cited by 22 · see citing works
Li, J., Jin, J., Li, S., Zhong, Y., Jin, Y., Zhang, X., Xia, B., Zhu, Y., Guo, R., Sun, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202202706 · Cited by 22 · see citing works
Self-citationDrugging cancer metabolism: Expectations vs. reality
Montrose, D. C., & Galluzzi, L. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.07.007 · Cited by 21 · see citing works
Serine synthesis influences tamoxifen response in ER+ human breast carcinoma
Metcalf, S. A., Petri, B. J., Kruer, T. L., Green, B., Dougherty, S. M., Wittliff, J. L., Klinge, C. M., & Clem, B. F. (2020) · Endocrine Related Cancer · doi:10.1530/erc-19-0510 · Cited by 21 · see citing works
De novo serine biosynthesis is protective in mitochondrial disease
Jackson, C. B., Marmyleva, A., Monteuuis, G., Awadhpersad, R., Mito, T., Zamboni, N., Tatsuta, T., Vincent, A. E., Wang, L., Khan, N. A., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115710 · Cited by 20 · see citing works
Dietary serine supplementation: Friend or foe?
Jiang, J., Li, B., He, W., & Huang, C. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.08.011 · Cited by 20 · see citing works
Targeting the Metabolic Adaptation of Metastatic Cancer
Tarragó‐Celada, J., & Cascante, M. (2021) · Cancers · doi:10.3390/cancers13071641 · Cited by 20 · see citing works
Sadiqa, A., Rasul, A., Hassan, M., Sultana, S., & Jabeen, F. (2022) · Molecules · doi:10.3390/molecules27186108 · Cited by 19 · see citing works
Predicting how drug molecules bind to their protein targets
Rachman, M. M., Barril, X., & Hubbard, R. E. (2018) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2018.07.001 · Cited by 19 · see citing works
Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH
Huang, Z., Zhang, K., Jiang, Y., Wang, M., Li, M., Guo, Y., Gao, R., Li, N., Wang, C., Chen, J., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.06.001 · Cited by 18 · see citing works
Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease
Chen, J., Hadi, F., Wen, X., Zhao, W., Xu, M., Xue, S., Lin, P., Calandrelli, R., Richard, J. L. C., Song, Z., et al. (2025) · Cell · doi:10.1016/j.cell.2025.03.045 · Cited by 19 · see citing works
Self-citationWang, Y., Zheng, M., Jiang, Q., Xu, Y., Zhou, X., Zhang, N., Sun, D., Li, H., & Chen, L. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.1c03215 · Cited by 17 · see citing works
Sánchez‐Castillo, A., & Kampen, K. R. (2024) · Discover Oncology · doi:10.1007/s12672-024-01544-6 · Cited by 17 · see citing works
Dimerization of PHGDH via the catalytic unit is essential for its enzymatic function
Xu, H., Qing, X., Wang, Q., Li, C., & Lai, L. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100572 · Cited by 17 · see citing works
Self-citationAmino acid metabolism in primary bone sarcomas
Jiménez, J. A., Lawlor, E. R., & Lyssiotis, C. A. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1001318 · Cited by 15 · see citing works
Zhao, N., Cao, Y., Tao, R., Zhu, X., Li, R., Chen, Y., Tao, K., Li, L., Chen, H., & Ma, X. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-2940 · Cited by 15 · see citing works
Fluctuation correlations as major determinants of structure- and dynamics-driven allosteric effects
Yu, M., Chen, Y.-X., Wang, Z.-L., & Liu, Z. (2019) · Physical Chemistry Chemical Physics · doi:10.1039/c8cp07859a · Cited by 14 · see citing works
Wang, Q., Zhang, X., Li, Q., Liu, X., Huang, Y., Cheng, S., Shinohara, H., Liu, Z., & Zhu, X. (2024) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2024.135286 · Cited by 14 · see citing works
Self-citationSpillier, Q., Ravez, S., Dochain, S., Vertommen, D., Thabault, L., Féron, O., & Frédérick, R. (2021) · Molecules · doi:10.3390/molecules26020477 · Cited by 14 · see citing works
Arlt, B., Mastrobuoni, G., Wünschel, J., Astrahantseff, K., Eggert, A., Kempa, S., & Deubzer, H. E. (2021) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2021.1935917 · Cited by 16 · see citing works
PHGDH inhibition and FOXO3 modulation drives PUMA-dependent apoptosis in osteosarcoma
Oyama, T., Brashears, C. B., Rathore, R., Benedict-Hamilton, H. M., Caldwell, K. E., Dirckx, N., Hawkins, W. G., & Tine, B. A. V. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07378-6 · Cited by 13 · see citing works
Serine metabolism in tumor progression and immunotherapy
Huang, D., Cai, H., & Huang, H. (2025) · Discover Oncology · doi:10.1007/s12672-025-02358-w · Cited by 13 · see citing works
Singh, M., Warita, K., Warita, T., Faeder, J. R., Lee, R., Sant, S., & Oltvai, Z. N. (2018) · Scientific Reports · doi:10.1038/s41598-018-27266-8 · Cited by 13 · see citing works
Sphingosine kinase 1 downregulation is required for adaptation to serine deprivation
Truman, J., Ruiz, C. F., Trayssac, M., Mao, C., Hannun, Y. A., & Obeid, L. M. (2021) · The FASEB Journal · doi:10.1096/fj.202001814rr · Cited by 12 · see citing works
Moonlighting functions of phosphoglycerate dehydrogenase in cancer
Wang, C., An, S., Zhao, L., Li, S., Huang, J., & Ren, W. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115940 · Cited by 11 · see citing works
Wang, Q., & Liu, Z.-M. (2021) · European Journal of Medicinal Chemistry Reports · doi:10.1016/j.ejmcr.2021.100003 · Cited by 11 · see citing works
Self-citationIdentification of benzo[b]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors
Cao, X., Li, X., Wang, F., Duan, Y., Wu, X., Lin, G., Geng, M., Huang, M., Tian, P., Tang, S., et al. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.107330 · Cited by 10 · see citing works
- Authors
- Wang, Q., Liberti, M. V., Liu, P., Deng, X., Liu, Y., Locasale, J. W., & Lai, L.
- Affiliations
- Peking University (CN)
- Duke University (US)
- Corresponding author
- Locasale, Jason W.
- Lai, Luhua
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 24
- Issue
- 1
- Pages
- 55-65
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC5915676
- OpenAlex
- W2564456364
- Cited by
- 147
- References
- 49
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 18 · 2023: 10 · 2022: 15 · 2021: 26 · 2020: 22 · 2019: 13 · 2018: 12 · 2017: 4
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Peking University
- National Natural Science Foundation of China (2016YFA0502303, 2015CB910300, 21633001)
- Ministerio de Ciencia y Tecnología
- National Science Foundation
- National Institutes of Health (R01CA193256, R00CA168997)
- College of Agricultural and Life Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- PHGDH, allosteric inhibition, serine biosynthesis, tumor metabolic reprogramming, virtual screening, tumor growth inhibition
- MeSH terms
- Allosteric Regulation, Allosteric Site, Antineoplastic Agents, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Humans, Models, Molecular, Serine, Structure-Activity Relationship, Tumor Cells, Cultured, Drug Design, Molecular Structure, Cell Proliferation, Phosphoglycerate Dehydrogenase
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