POMHEX is a cell-permeable POM prodrug of HEX, a specific inhibitor of enolase 2 (ENO2). POMHEX can be used in studies related to ENO1-deficient cancers such as glioblastoma (GBM) and glycolytic metabolic reprogramming[1-4].
In vitro, POMHEX (35–50nM) was applied to oligodendroglioma cells (SF10417, BT88, BT54, TS603, NCH612) for 72 hours. POMHEX inhibited ENO2-dependent enolase activity, suppressed cell proliferation, and arrested cell cycle progression[5]. POMHEX (10μM) was applied to bevacizumab-resistant/regorafenib-resistant colorectal cancer cells (HCT116, SW620) for 24 hours. POMHEX reduced intracellular levels of the ENO2-derived metabolite phosphoenolpyruvate (PEP) and downregulated signaling along the PEP–HDAC1–β-catenin axis, thereby inhibiting β-catenin transcriptional activity. When combined with anti-angiogenic agents (bevacizumab/regorafenib), POMHEX further impaired the survival of drug-resistant cells[6].
In vivo, POMHEX (10mg/kg; once weekly; intra-articular injection) was administered to C57BL/6J mice for 16 consecutive weeks. POMHEX alleviated cartilage destruction and matrix loss in age-related osteoarthritis, maintained cartilage proteoglycan content and anabolic phenotype, suppressed catabolic expression including MMP3/MMP13, reduced osteophyte formation and improved subchondral bone microstructural changes, and relieved pain abnormalities[7]. POMHEX (20mg/kg; intraperitoneal injection; every other day) combined with bevacizumab (10mg/kg; intraperitoneal injection; twice weekly) was given to BALB/c nude mice bearing subcutaneous xenografts of bevacizumab-resistant HCT116 colorectal cancer for 15 days. The combination of POMHEX and bevacizumab inhibited tumor growth, reduced Ac-K49-β-catenin signaling activity in tumor tissues, decreased Ki67-positive proliferating cells and CD31-positive microvessel density, and increased cleaved caspase-3-positive apoptotic signals[8].
References:
[1] Yan VC, Pham CD, Ballato ES, et al. Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers. J Med Chem. 2022 Oct 27;65(20):13813-13832.
[2] Yan VC, Barekatain Y, Lin YH, et al. Comparative Pharmacology of a Bis-Pivaloyloxymethyl Phosphonate Prodrug Inhibitor of Enolase after Oral and Parenteral Administration. ACS Pharmacol Transl Sci. 2023 Jan 6;6(2):245-252.
[3] Roster CP, LaVigne D, Milanes JE, et al. Enolase Inhibitors as Early Lead Therapeutics against Trypanosoma brucei. Pathogens. 2023 Oct 28;12(11):1290.
[4] Wang Q, Lang Z, Yin G, et al. Analysis on the involvement of phosphoglycerate mutase 1 in the aerobic glycolysis of melanoma cells. Int J Biol Macromol. 2024 Dec;283(Pt 4):137898.
[5] Udutha S, Batsios G, Taglang C, et al. The 1p/19q co-deletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas. Neuro Oncol. 2026 Mar 21:noag063.
[6] Wang C, Huang M, Lin Y, et al. ENO2-derived phosphoenolpyruvate functions as an endogenous inhibitor of HDAC1 and confers resistance to antiangiogenic therapy. Nat Metab. 2023 Oct;5(10):1765-1786.
[7] Lin YH, Satani N, Hammoudi N, et al. An enolase inhibitor for the targeted treatment of ENO1-deleted cancers. Nat Metab. 2020 Dec;2(12):1413-1426.
[8] Hua F, Nan J, Wu R, et al. Enolase 2-mediated lactylation-dependent disruption of the GNL3-MDM2-p53 axis in age-related osteoarthritis. Cell Mol Biol Lett. 2026 May 26.