Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors

Hong, Lin; Zhang, Jin; Xie, Ren; Schulz, Mark J.; Tedesco, Rosanna; Qu, Junya; Erhard, Karl F.; Mack, James F.; Raha, Kaushik; Rendina, Alan R.; Szewczuk, Lawrence M.; Kratz, Patricia M.; Jurewicz, Anthony J.; Cecconie, Ted; Martens, Stan; McDevitt, Patrick; Martin, John D.; Chen, Stephenie B.; Jiang, Yong Mei; Nickels, Leng; Schwartz, Benjamin J.; Smallwood, Angela; Zhao, Baoguang; Campobasso, Nino; Qian, Yanqiu; Briand, Jacques; Rominger, Cynthia M.; Oleykowski, Catherine A.; Hardwicke, Mary Ann; Luengo, Juan I.

doi:10.1021/acsmedchemlett.5b00214

Cited by 68 publications

(58 citation statements)

References 13 publications

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“…With extensive studies, including the present investigation, showing that HK2 is a master promoting factor in different stages of carcinogenesis ( Supplementary Table 4), much efforts were put in exploring HK-mediated tumor inhibitors, despite that no potent drugs targeting HK2 are yet available in clinic (80)(81)(82)(83)(84). Taking the most promising HK2-targeting drug, 3-bromopyruvate (3-BP), as an example, although single treatment of 3-BP, at the appropriate dose and formulation, could effectively destroy glycolytic tumors and seems to be non-toxic to all sorts of vertebrates, certain failure cases were still reported in clinical test (83).…”

Section: Discussionmentioning

confidence: 98%

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Huang²,

Hsieh³

et al. 2020

Front. Oncol.

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To support great demand of cell growth, cancer cells preferentially obtain energy and biomacromolecules by glycolysis over mitochondrial oxidative phosphorylation (OxPhos). Among all glycolytic enzymes, hexokinase (HK), a rate-limiting enzyme at the first step of glycolysis to catalyze cellular glucose into glucose-6-phosphate, is herein emphasized. Four HK isoforms, HK1-HK4, were discovered in nature. It was shown that HK2 expression is enriched in many tumor cells and correlated with poorer survival rates in most neoplastic cells. HK2-mediated regulations for cell malignancy and mechanistic cues in regulating head and neck tumorigenesis, however, are not fully elucidated. Cellular malignancy index, such as cell growth, cellular motility, and treatment sensitivity, and molecular alterations were determined in HK2-deficient head and neck squamous cell carcinoma (HNSCC) cells. By using various cancer databases, HK2, but not HK1, positively correlates with HNSCC progression in a stage-dependent manner. A high HK2 expression was detected in head and neck cancerous tissues compared with their normal counterparts, both in mouse and human subjects. Loss of HK2 in HNSCC cells resulted in reduced cell (in vitro) and tumor (in vivo) growth, as well as decreased epithelial-mesenchymal transition-mediated cell movement; in contrast, HK2-deficient HNSCC cells exhibited greater sensitivity to chemotherapeutic drugs cisplatin and 5-fluorouracil but are more resistant to photodynamic therapy, indicating that HK2 expression could selectively define treatment sensitivity in HNSCC cells. At the molecular level, it was found that HK2 alteration drove metabolic reprogramming toward OxPhos and modulated oncogenic Akt and mutant TP53-mediated signals in HNSCC cells. In summary, the present study showed that HK2 suppression could lessen HNSCC oncogenicity and modulate therapeutic sensitivity, thereby being an ideal therapeutic target for HNSCCs.

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Section: Discussionmentioning

confidence: 98%

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Huang²,

Hsieh³

et al. 2020

Front. Oncol.

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“…Previous HK2 shRNA knockdown studies in HK1 1 HK2 1 cell lines from breast (10), lung (10), prostate (12), pancreatic (11), and brain (13) tumors reported HK2 knockdown inhibited cancer cell proliferation in culture and xenograft tumor progression and suggested HK2 as a potential global cancer therapeutic target. However, using both those same shHK2 sequences (11)(12)(13)(14) and shHK2 sequences we designed that have greater efficacy in reducing HK2 levels, we did not observe significant differences in cell proliferation, colony formation, or xenograft tumor growth in these cancer cells when HK2 expression was silenced, despite substantial differences in glucose consumption.…”

Section: Discussionmentioning

confidence: 80%

Hexokinase 2 Is Targetable for HK1-Negative, HK2-Positive Tumors from a Wide Variety of Tissues of Origin

Catapang

Doh

et al. 2018

J Nucl Med

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Incr eased aerobic glycolysis-the Warburg Effect (1)-has been associated with cancer for 90 y. The hexokinases (HKs), the first enzymes committed to glycolysis, convert glucose to glucose-6-phosphate. There are 4 HK isoforms, HK1-HK4 (2). Most adult tissues express only HK1. Muscle and adipose tissue use HK2 for glycolysis; liver and pancreatic b-cells express HK4 (also called glucokinase) and do not express HK1 or HK2. In contrast to normal tissues, many tumors express both HK1 and HK2. Elevated hexokinase activity as a driver of tumor glycolysis was reported in the late 1970s (3); however, it was about 30 y later until HK2 expression was identified in most cancers (4). No cancer therapy based on interventions directed at elevated tumor glycolysis is approved for clinical use. Development of the positron-emitting glucose analog 18 F-FDG (5) and PET technology (6) led, in the late 1970s/early 1980s, to 18 F-FDG PET clinical applications to study, noninvasively, glucose metabolism in the brain (7), heart (8), and cancer (9). HK2 is a likely major contributor to the increased conversion of 18 F-FDG to 18 F-FDG-6P in most tumors. 18 F-FDG PET oncologic clinical imaging has played a major role in cancer diagnosis, metastasis detection, monitoring disease progression, and both selection and modification of therapeutic protocols. Cell culture and xenograft tumor data from human breast (10), lung (10), pancreatic (11), and prostate (12) cancer and glioblastoma (13) have been interpreted to suggest that selective HK2 inhibition has potential to be a near-globally effective cancer therapeutic. Moreover, global HK2 deletion in adult mice is tolerated (10). These data have stimulated intense interest in development of selective HK2 inhibitors for cancer therapy. Enthusiasm has been substantially elevated by description of small-molecule inhibitors with preference for HK2 over HK1 (14). However, no laboratory has directly compared the roles of HK1 and HK2 in tumor progression and 18 F-FDG PET imaging. Here we find that HK1-positive/HK2-positive (HK1 1 HK2 1) cancers can tolerate HK2 silencing. Although HK1 1 HK2 1 xenograft tumor progression is unaffected by HK2 deletion, 18 F-FDG PET signal is significantly reduced. Moreover, subsets of cancers from a variety of tissues of origin express HK2 but not HK1 and are sensitive to HK2 silencing-induced inhibition of cell proliferation in culture and suppression of xenograft tumor growth.

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“…These findings demonstrate the importance of aerobic glycolysis in development and cancer, suggesting that blocking glycolysis through HK2 inhibition may produce a clinically significant anti-tumor effect. Development of selective HK2 inhibitors for anti-cancer therapy however, has been problematic (16). Whether targeting glycolysis downstream of HK2 would similarly inhibit tumor growth is unknown.…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

et al. 2017

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Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNPs), and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of Hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting Pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which post-mitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM.

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Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors

Cited by 68 publications

References 13 publications

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis

Hexokinase 2 Is Targetable for HK1-Negative, HK2-Positive Tumors from a Wide Variety of Tissues of Origin

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

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