Novel selective hexokinase 2 inhibitor Benitrobenrazide blocks cancer cells growth by targeting glycolysis

Zheng, Mengzhu; Wu, Canrong; Yang, Kaiyin; Yang, Yueying; Liu, Yang; Gao, Suyu; Wang, Qiqi; Li, Chen; Chen, Lixia; Li, Hua

doi:10.1016/j.phrs.2020.105367

Cited by 62 publications

(50 citation statements)

References 23 publications

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“…Another putative HK2 selective inhibitor with sub-micromolar potency, benitrobenrazide 69 , was developed from a lead compound identified through virtual ligand screening of six million compounds using the crystal structure of HK2. Oral administration of benitrobenrazide demonstrated efficacy in two tumour xenograft models in immunocompromised mice 70 .…”

Section: Aerobic Glycolysismentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

625

402

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Before Sidney Farber published his seminal paper in 1948 in The New England Journal of Medicine describing anti-folate-induced remissions 1 , childhood acute lymphocytic leukaemia (ALL) was universally fatal. Thirty years before this article was published, Otto Warburg's determination to conquer cancer led him to discover that many tumours used aerobic glycolysis (also known as the Warburg effect) to convert almost all glucose to lactate even in the presence of oxygen 2 . Aerobic glycolysis, however, has never been successfully exploited clinically, particularly as the use of 2-deoxyglucose, which inhibits glycolysis, was proved to have undesirable side effects and limited efficacy in humans 3 . Farber noted the clinical 'accelerated phenomenon' among 11 children treated with an active form of folate, pteroyltriglutamic acid, which was thought to have broad anticancer activity, and thus sought folate antagonists as therapeutic agents. Working with chemist Yellapragada Subbarow, the anti-folate aminopterin was synthesized, and Farber was able to induce remissions in children with ALL, thus providing the foundation for cancer chemotherapy 4 . Today, another folate antagonist, methotrexate, is still used in the multi-chemotherapy treatment of childhood ALL and, used together with l-asparaginase, induces a remarkable 90% cure rate. Indeed, many anti-metabolite drugs, particularly those targeting nucleotide metabolism, have been approved and used in the clinic (Table 1). The recent approval of drugs that target mutant isocitrate dehydrogenases in acute myeloid leukaemias (AMLs) (Table 1) provides a milestone in targeting cancer metabolism with precision and establishes that metabolic therapy can be highly effective.Warburg's and Farber's ideas were conceptually displaced in the 1980s as oncogenes and tumour suppressors became recognized as targets in human cancer treatments. Molecular biology took centre stage, and the drive to target oncogenes began with vigour, resulting in many effective anticancer kinase drugs that displaced interest in targeting metabolism. However, the links between oncogenes, tumour suppressors and metabolism began to emerge in the 1990s, ushering in a resurgence of interest in cancer metabolism [5][6][7] . More recently, the success of immunotherapy underscores the importance of non-cancer-cell autonomous components of the tumour immune microenvironment (TIME) [8][9][10] , which is a neoplastic hub of metabolically active cells comprising tumour cells, immune cells, stromal cells and blood and lymph vessel cells, all of which are involved in tumour growth. In this regard, targeting cancer metabolism must be based on a thorough understanding of how inhibiting specific metabolic pathways affects the TIME cells, which can either dampen or promote tumour progression. In this Review, we cover the fundamentals of cancer metabolism and focus on recent small-molecule drug discovery efforts to target cancer.

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Section: Aerobic Glycolysismentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

625

402

View full text Add to dashboard Cite

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“…To date, different types of HK2 inhibitors have been developed ( 27 ). For instance, the selective HK2 inhibitor Benitrobenrazide binds directly to HK2, blocks glycolysis, and induces apoptosis in HK2-overexpressing cancer cells ( 28 ). Glycolysis is activated in radioresistant CC cells, and inhibiting glycolysis with HK2 inhibitor 2-DG improves the sensitivity of radioresistant CC cells to irradiation ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

HK2 Is a Crucial Downstream Regulator of miR-148a for the Maintenance of Sphere-Forming Property and Cisplatin Resistance in Cervical Cancer Cells

et al. 2021

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The acquisition of cancer stem-like properties is believed to be responsible for cancer metastasis and therapeutic resistance in cervical cancer (CC). CC tissues display a high expression level of hexokinase 2 (HK2), which is critical for the proliferation and migration of CC cells. However, little is known about the functional role of HK2 in the maintenance of cancer stem cell-like ability and cisplatin resistance of CC cells. Here, we showed that the expression of HK2 is significantly elevated in CC tissues, and high HK2 expression correlates with poor prognosis. HK2 overexpression (or knockdown) can promote (or inhibit) the sphere-forming ability and cisplatin resistance in CC cells. In addition, HK2-overexpressing CC cells show enhanced expression of cancer stem cell-associated genes (including SOX2 and OCT4) and drug resistance-related gene MDR1. The expression of HK2 is mediated by miR-145, miR-148a, and miR-497 in CC cells. Overexpression of miR-148a is sufficient to reduce sphere formation and cisplatin resistance in CC cells. Our results elucidate a novel mechanism through which miR-148a regulates CC stem cell-like properties and chemoresistance by interfering with the oncogene HK2, providing the first evidence that dysregulation of the miR-148a/HK2 signaling plays a critical role in the maintenance of sphere formation and cisplatin resistance of CC cells. Our findings may guide future studies on therapeutic strategies that reverse cisplatin resistance by targeting this pathway.

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“…As a result, many novel potent inhibitors of glycolytic enzymes have been identified and their anti-cancer properties elucidated [ 8 , 16 , 23 , 24 ]. Many of these enzymes, including GLUT1 [ 25 , 26 ], hexokinase II [ 27 ], GAPDH [ 28 , 29 ], lactate dehydrogenase [ 22 ], etc., are attractive targets for anti-cancer drug development and are currently in clinical or pre-clinical investigations [ 19 ]. In our study, we observed that MSPA forms most the stable complex with ENO1 ( Figure 5 B, Supplementary Figures S4–S7 ), and can significantly inhibit the enzyme activity of purified ENO1 ( Supplementary Figure S2 ).…”

Section: Discussionmentioning

confidence: 99%

Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

et al. 2021

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Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.

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Novel selective hexokinase 2 inhibitor Benitrobenrazide blocks cancer cells growth by targeting glycolysis

Cited by 62 publications

References 23 publications

Targeting cancer metabolism in the era of precision oncology

Targeting cancer metabolism in the era of precision oncology

HK2 Is a Crucial Downstream Regulator of miR-148a for the Maintenance of Sphere-Forming Property and Cisplatin Resistance in Cervical Cancer Cells

Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

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