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The activation of alternative cholesterol export routes that can bypass NPC1\/2 deficiency could provide therapeutic opportunities. We previously demonstrated that gene depletion of the Rab7-GTPase activating protein (GAP) TBC1D15, which hydrolyses active GTP-bound Rab7, led to elevated Rab7-GTP levels. This enabled cholesterol export from LE\/Lys to reduce cholesterol accumulation in NPC1 mutant cells. Here we aimed to pharmacologically interfere with TBC1D15-mediated Rab7 inactivation to upregulate Rab7 activity and reduce cholesterol accumulation in NPC1 mutant models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The protein structure of the GAP domain of human TBC1D15 in complex with human Rab7-GTP served to perform in silico drug screening and identify small molecules with potentially high TBC1D15 binding affinity. Rab-GTP pulldown assays and fluorescence microscopy analyzed the ability of drug candidates to elevate Rab7-GTP levels and reduce cholesterol accumulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Four drug candidates reduced cholesterol accumulation in NPC1 mutant Chinese Hamster Ovary (CHO) M12 cells, NPC1 patient fibroblasts as well as differentiated SH-SY5Y neuronal cells and three-dimensional brain organoids treated with U18666A, a pharmacological NPC1 inhibitor. This was associated with elevated Rab7-GTP levels in drug-treated M12 and NPC1 patient fibroblasts. Moreover, drug candidates augmented 2-hydroxypropyl-\u03b2-cyclodextrin (HP\u03b2CD)-induced cholesterol removal from U18666A-treated SH-SY5Y cells. Notably, drug candidates did not negatively impact on cell viability or cause membrane damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Advancing small molecules that can elevate Rab7-GTPase activity could provide opportunities to overcome cholesterol transport defects in NPC mutant cells and offer applications in other Rab7-related neurological diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11095-026-04058-8","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T22:34:24Z","timestamp":1772577264000},"page":"1009-1031","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Small Molecules to Elevate Rab7-GTPase Activity and Lower Cholesterol Accumulation in Niemann-Pick Type C Disease"],"prefix":"10.1007","volume":"43","author":[{"given":"Mai K. 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