Discovery of compound 1105486 as a selective inhibitor of B4GALT1: potential for pancreatic cancer therapy
Targeting aberrant β-1,4-galactosyltransferase 1 (B4GALT1) activity represents an unexplored therapeutic avenue for pancreatic ductal adenocarcinoma (PDAC). Guided by a concise active-learning structure-based workflow, we rapidly triaged 22.6 million compounds and singled out 1105486 for experimenta...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2025.1651402/full |
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| author | Xu Yunyun Mou Yiping |
| author_facet | Xu Yunyun Mou Yiping |
| author_sort | Xu Yunyun |
| collection | DOAJ |
| description | Targeting aberrant β-1,4-galactosyltransferase 1 (B4GALT1) activity represents an unexplored therapeutic avenue for pancreatic ductal adenocarcinoma (PDAC). Guided by a concise active-learning structure-based workflow, we rapidly triaged 22.6 million compounds and singled out 1105486 for experimental characterization. In PANC-1 cells, the molecule suppressed proliferation with an IC50 of 19.8 ± 1.3 µM, while hTERT-HPNE epithelial cells retained >95% viability at concentrations up to 80 μM, indicating an encouraging initial safety window. Mechanistically, 1105486 engages the UDP-galactose pocket through stable hydrogen bonds to ARG187 and GLU313, a binding mode corroborated by 1 µs molecular-dynamics simulations and MM/GBSA energetics. Unlike previously reported glycosyltransferase inhibitors, which often lack selectivity and may affect multiple family members, 1105486 specifically targets B4GALT1 with high selectivity, occupying its unique catalytic pocket. To our knowledge, 1105486 constitutes the first reported small-molecule inhibitor of B4GALT1 and establishes a tractable chemical scaffold for optimization toward sub-micromolar potency and in vivo evaluation. The compound’s selective cytotoxic profile, promising physicochemical properties, and the potential for further development highlight its in vivo efficacy and its role as a lead candidate for the next-generation of glycosylation-directed therapeutics for PDAC. |
| format | Article |
| id | doaj-art-e6a5744870ed448bbb72d70ccf7d49d5 |
| institution | Kabale University |
| issn | 2296-2646 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj-art-e6a5744870ed448bbb72d70ccf7d49d52025-08-20T03:59:45ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462025-08-011310.3389/fchem.2025.16514021651402Discovery of compound 1105486 as a selective inhibitor of B4GALT1: potential for pancreatic cancer therapyXu YunyunMou YipingTargeting aberrant β-1,4-galactosyltransferase 1 (B4GALT1) activity represents an unexplored therapeutic avenue for pancreatic ductal adenocarcinoma (PDAC). Guided by a concise active-learning structure-based workflow, we rapidly triaged 22.6 million compounds and singled out 1105486 for experimental characterization. In PANC-1 cells, the molecule suppressed proliferation with an IC50 of 19.8 ± 1.3 µM, while hTERT-HPNE epithelial cells retained >95% viability at concentrations up to 80 μM, indicating an encouraging initial safety window. Mechanistically, 1105486 engages the UDP-galactose pocket through stable hydrogen bonds to ARG187 and GLU313, a binding mode corroborated by 1 µs molecular-dynamics simulations and MM/GBSA energetics. Unlike previously reported glycosyltransferase inhibitors, which often lack selectivity and may affect multiple family members, 1105486 specifically targets B4GALT1 with high selectivity, occupying its unique catalytic pocket. To our knowledge, 1105486 constitutes the first reported small-molecule inhibitor of B4GALT1 and establishes a tractable chemical scaffold for optimization toward sub-micromolar potency and in vivo evaluation. The compound’s selective cytotoxic profile, promising physicochemical properties, and the potential for further development highlight its in vivo efficacy and its role as a lead candidate for the next-generation of glycosylation-directed therapeutics for PDAC.https://www.frontiersin.org/articles/10.3389/fchem.2025.1651402/fullPDACB4GALT1active-learningcomputational-experimental integrationcytotoxicity safety window |
| spellingShingle | Xu Yunyun Mou Yiping Discovery of compound 1105486 as a selective inhibitor of B4GALT1: potential for pancreatic cancer therapy Frontiers in Chemistry PDAC B4GALT1 active-learning computational-experimental integration cytotoxicity safety window |
| title | Discovery of compound 1105486 as a selective inhibitor of B4GALT1: potential for pancreatic cancer therapy |
| title_full | Discovery of compound 1105486 as a selective inhibitor of B4GALT1: potential for pancreatic cancer therapy |
| title_fullStr | Discovery of compound 1105486 as a selective inhibitor of B4GALT1: potential for pancreatic cancer therapy |
| title_full_unstemmed | Discovery of compound 1105486 as a selective inhibitor of B4GALT1: potential for pancreatic cancer therapy |
| title_short | Discovery of compound 1105486 as a selective inhibitor of B4GALT1: potential for pancreatic cancer therapy |
| title_sort | discovery of compound 1105486 as a selective inhibitor of b4galt1 potential for pancreatic cancer therapy |
| topic | PDAC B4GALT1 active-learning computational-experimental integration cytotoxicity safety window |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2025.1651402/full |
| work_keys_str_mv | AT xuyunyun discoveryofcompound1105486asaselectiveinhibitorofb4galt1potentialforpancreaticcancertherapy AT mouyiping discoveryofcompound1105486asaselectiveinhibitorofb4galt1potentialforpancreaticcancertherapy |