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dc.contributor.authorRohde, Jason M.
dc.contributor.authorBrimacombe, Kyle R.
dc.contributor.authorLiu, Li
dc.contributor.authorPacold, Michael Edward
dc.contributor.authorYasgar, Adam
dc.contributor.authorCheff, Dorian M.
dc.contributor.authorLee, Tobie D.
dc.contributor.authorRai, Ganesha
dc.contributor.authorBaljinnyam, Bolormaa
dc.contributor.authorLi, Zhuyin
dc.contributor.authorSimeonov, Anton
dc.contributor.authorHall, Matthew D.
dc.contributor.authorShen, Min
dc.contributor.authorSabatini, David
dc.contributor.authorBoxer, Matthew B.
dc.date.accessioned2020-05-22T19:23:24Z
dc.date.available2020-05-22T19:23:24Z
dc.date.issued2018-05
dc.identifier.issn0968-0896
dc.identifier.urihttps://hdl.handle.net/1721.1/125424
dc.description.abstractProliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhibitors of human PHGDH. Feedback inhibition was minimized by coupling PHGDH activity to two downstream enzymes (PSAT1 and PSPH), providing a marked improvement in enzymatic turnover. Further coupling of NADH to a diaphorase/resazurin system enabled a red-shifted detection readout, minimizing interference due to compound autofluorescence. With this protocol, over 400,000 small molecules were screened for PHGDH inhibition, and following hit validation and triage work, a piperazine-1-thiourea was identified. Following rounds of medicinal chemistry and SAR exploration, two probes (NCT-502 and NCT-503) were identified. These molecules demonstrated improved target activity and encouraging ADME properties, enabling in vitro assessment of the biological importance of PHGDH, and its role in the fate of serine in PHGDH-dependent cancer cells. This manuscript reports the assay development and medicinal chemistry leading to the development of NCT-502 and -503 reported in Pacold et al. (2016). Keywords: PHGDH; inhibitor; serineen_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant U54MH084681)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (R37 AI047389)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (R01 CA103866)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (R01 CA129105)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (R37 AI047389)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (K22 CA212059)en_US
dc.description.sponsorshipMary Kay Foundation (017-32)en_US
dc.description.sponsorshipV foundation (V2017-004)en_US
dc.language.isoen
dc.publisherElsevier BVen_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/j.bmc.2018.02.016en_US
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs Licenseen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.sourcePMCen_US
dc.titleDiscovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitorsen_US
dc.typeArticleen_US
dc.identifier.citationRohde, Jason M. et al. “Discovery and Optimization of Piperazine-1-Thiourea-Based Human Phosphoglycerate Dehydrogenase Inhibitors.” Bioorganic & Medicinal Chemistry 26, 8 (May 2018): 1727–39.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.relation.journalBioorganic & Medicinal Chemistryen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2020-05-11T15:47:47Z
dspace.date.submission2020-05-11T15:47:50Z
mit.journal.volume26en_US
mit.journal.issue8en_US
mit.licensePUBLISHER_CC


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