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We designed a spiro scaffold composed of a cyclic imide and a diazepane to construct a focused compound library with minimal diversity. Screening for HCT\u2010116 cell growth inhibition, supported by growth curve analysis and structural optimization, identified compounds\n                    <jats:bold>1a<\/jats:bold>\n                    and\n                    <jats:bold>2a<\/jats:bold>\n                    as a chemical probe and a lead candidate, respectively. Compound\n                    <jats:bold>2a<\/jats:bold>\n                    displayed a distinctive gene expression profile and reduced the viability of U251 cells within the JFCR39 cancer cell panel. A fluorescent probe derived from\n                    <jats:bold>1a<\/jats:bold>\n                    , localized to the cell membrane, provided crucial information for cell lysate preparation and the affinity\u2010based identification of facilitative glucose transporter type 1 (GLUT1) as a candidate target protein. Resistance to\n                    <jats:bold>2a<\/jats:bold>\n                    was linked to a mutation at position N411 in GLUT1, and cells expressing the GLUT1\n                    <jats:sup>N411K<\/jats:sup>\n                    mutant showed marked attenuation of both antiproliferative and glucose\u2010uptake inhibitory activities. In this study, we discuss the impact of an integrated approach from hit compound discovery to target identification, as well as\n                    <jats:bold>2a<\/jats:bold>\n                    , a notable GLUT1 inhibitor that exhibits robust activity attributable solely to GLUT1 inhibition.\n                  <\/jats:p>","DOI":"10.1002\/cbic.70556","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:59:24Z","timestamp":1791309564000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemical Biology\u2010Based Drug Discovery Workflow Highlights Target Identification as a Key Step in Developing a Novel, Potent, and Selective GLUT1 Inhibitor"],"prefix":"10.1002","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8010-8781","authenticated-orcid":false,"given":"Hiroshi","family":"Kamiyama","sequence":"first","affiliation":[{"name":"Tsukuba Research Laboratories Eisai Co., Ltd.  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