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POMHEX Sale

目录号 : GC62487

POMHEX 是一个消旋混合物,是具有细胞渗透性的 HEX 的 POM 前体药物,是ENO2 的特异性抑制剂。POMHEX 对ENO1 缺失的细胞表现出低纳摩尔级别活性,并对 ENO1 缺失的肿瘤模型表现出良好的抗癌效果。POMHEX 是有效的糖酵解抑制剂。

POMHEX Chemical Structure

Cas No.:2004714-34-3

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥3,465.00
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5mg
¥3,150.00
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10mg
¥5,600.00
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25mg
¥11,550.00
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50mg
¥17,850.00
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产品描述

POMHEX, a racemic mixture and a cell-permeable pivaloyloxymethyl (POM) prodrug of HEX, is a potent, ENO2-specific inhibitor of enolase. POMHEX exhibits low-nanomolar potency against ENO1-deleted cells in vitro and is capable of eradicating ENO1-deleted xenografted tumours in vivo. POMHEX is a potent glycolysis inhibitor[1].

POMHEX (78 nM, 8h) minimally impacts ENO1-WT glioma cells but profoundly affected ENO1-deleted cells[1].POMHEX (0-720 nM) selectively induces energy stress, inhibits proliferation and triggers apoptosis in ENO1-deleted glioma cells[1].

POMHEX (i.v., ip) injections are consistently tolerated without haemolytic anaemia at doses of up to 10 mg per kg (body weight) per day. POMHEX (i.v., 35 mg/kg) results in lethargy that prompted veterinarians to perform euthanasia[1].POMHEX is rapidly hydrolysed to HemiPOMHEX in mouse plasma ex vivo, with a half-lifeof approximately 30 s, the half-life in human blood ex vivo was about 9min[1].

[1]. Yu-Hsi Lin, et al. An enolase inhibitor for the targeted treatment of ENO1-deleted cancers. Nat Metab. 2020 Nov 23.

Chemical Properties

Cas No. 2004714-34-3 SDF
分子式 C17H30NO9P 分子量 423.4
溶解度 DMSO : 100 mg/mL (236.18 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mM 2.3618 mL 11.8092 mL 23.6183 mL
5 mM 0.4724 mL 2.3618 mL 4.7237 mL
10 mM 0.2362 mL 1.1809 mL 2.3618 mL
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Research Update

An enolase inhibitor for the targeted treatment of ENO1-deleted cancers

Nat Metab 2020 Dec;2(12):1413-1426.PMID:33230295DOI:10.1038/s42255-020-00313-3.

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.

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.PMID:36251833DOI:10.1021/acs.jmedchem.2c01039.

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of 5, exhibited low micromolar IC50 values in ENO1-deleted glioma cells and improved stability in human serum over 6. The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation.

Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma

Cancer Metab 2021 Jun 25;9(1):27.PMID:34172075DOI:10.1186/s40170-021-00259-4.

Background: Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates and must be replenished (anaplerosis), mainly from pyruvate and glutamine. We recently described a novel enolase inhibitor, HEX, and its pro-drug POMHEX. Since glycolysis inhibition would deprive the cell of a key source of pyruvate, we hypothesized that enolase inhibitors might inhibit anaplerosis and synergize with other inhibitors of anaplerosis, such as the glutaminase inhibitor, CB-839. Methods: We analyzed polar metabolites in sensitive (ENO1-deleted) and resistant (ENO1-WT) glioma cells treated with enolase and glutaminase inhibitors. We investigated whether sensitivity to enolase inhibitors could be attenuated by exogenous anaplerotic metabolites. We also determined the synergy between enolase inhibitors and the glutaminase inhibitor CB-839 in glioma cells in vitro and in vivo in both intracranial and subcutaneous tumor models. Results: Metabolomic profiling of ENO1-deleted glioma cells treated with the enolase inhibitor revealed a profound decrease in the TCA cycle metabolites with the toxicity reversible upon exogenous supplementation of supraphysiological levels of anaplerotic substrates, including pyruvate. ENO1-deleted cells also exhibited selective sensitivity to the glutaminase inhibitor CB-839, in a manner rescuable by supplementation of anaplerotic substrates or plasma-like media PlasmaxTM. In vitro, the interaction of these two drugs yielded a strong synergistic interaction but the antineoplastic effects of CB-839 as a single agent in ENO1-deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood-brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors. Conclusion: Together, these data suggest that at least for ENO1-deleted gliomas, tumors in vivo-unlike cells in culture-show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of in vitro culture and suggest that cell culture media nutrient composition more faithful to the in vivo environment will more accurately predict in vivo efficacy of metabolism targeting drugs.

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.PMID:PMC9926520DOI:10.1021/acsptsci.2c00216.

Metabolically labile prodrugs can experience stark differences in catabolism incurred by the chosen route of administration. This is especially true for phosph(on)ate prodrugs, in which successive promoiety removal transforms a lipophilic molecule into increasingly polar compounds. We previously described a phosphonate inhibitor of enolase (HEX) and its bis-pivaloyloxymethyl ester prodrug (POMHEX) capable of eliciting strong tumor regression in a murine model of enolase 1 (ENO1)-deleted glioblastoma following parenteral administration. Here, we characterize the pharmacokinetics and pharmacodynamics of these enolase inhibitors in vitro and in vivo after oral and parenteral administration. In support of the historical function of lipophilic prodrugs, the bis-POM prodrug significantly improves cell permeability of and rapid hydrolysis to the parent phosphonate, resulting in rapid intracellular loading of peripheral blood mononuclear cells in vitro and in vivo. We observe the influence of intracellular trapping in vivo on divergent pharmacokinetic profiles of POMHEX and its metabolites after oral and parenteral administration. This is a clear demonstration of the tissue reservoir effect hypothesized to explain phosph(on)ate prodrug pharmacokinetics but has heretofore not been explicitly demonstrated.