Table 3.

Therapeutic compounds or drugs and targets within cancer metabolism.

Metabolism	Compound or Drug	Target	Mechanism	Findings	Clinical Pipeline	Reference
Glycolysis	3-Bromopyruvate	Hexokinase II	Irreversibly alkylates HK2, resulting in the disruption of glucose metabolism, leading to cancer cell death	3-BP (20 mg/kg) reduced tumor size by 75–80% in animals and induced apoptosis and necrosis in drug-treated tumor tissues	Animal Studies	[128]
TCA cycle	6-Methoxydihydroavicine (6-ME)	Oxaloacetic Acid Metabolism	Disrupts OAA metabolism, leading to ROS accumulation and resulting in disrupted mitochondrial homeostasis, ultimately driving apoptosis in ovarian cancer cells	6-ME significantly reduced tumor growth in a nude mouse model of ovarian cancer without causing physiologically harmful effects on the animal	Animal Studies	[129]
Glycolysis	AZD3965	MCT-1	Inhibition of MCT1-mediated lactic acid efflux during T-cell lymphocyte proliferation	The drug showed rapid oral absorption, nearly complete bioavailability, nonlinear pharmacokinetics, and potential involvement in enterohepatic circulation (EHC), with evidence of target-mediated drug disposition (TMDD)	Phase I	[130]
Glycolysis	Benserazide (Benz)	Hexokinase II	Competitive and noncompetitive binding to selectively inhibit HK2	In vivo, it suppresses tumor growth in mice without toxicity; when formulated as liposomal nanoparticles, Benz enhances tumor targeting and efficacy at lower doses	Animal Studies	[131]
Glutaminolysis	CB839 (Telaglenastat)	Glutamine oxidase	Block glutamine-to-glutamate conversion, reducing the number of immunosuppressive cells and reshaping the tumor microenvironment	The study established a recommended phase II dose (RP2D) for telaglenastat, demonstrating safety, strong GLS inhibition, and early anticancer activity, prompting further investigation	Phase I	[132]
Glycolysis	Curcumin (Cur) + Thymoquinone (TQ)	Caspase-3 and PI3K/AKT	Induces apoptosis and cell cycle arrest, and decreases proliferation, colony formation, and migration of MCF7 and MDA-MB-231 cells	Cur and TQ significantly inhibited cancer cell growth and migration, increased apoptosis (73.96% for Cur, 75.76% for Cur + TQ), and reduced S-phase values compared to controls	In vitro	[133]
Glycolysis	Demethylzeylasteral (DML)	Lactate	Dose-dependent decrease in intracellular lactate levels Regulation of histone acetylation via H3K9la and H3K56la modification sites	DML treatment significantly inhibited tumor growth in vivo, as shown by slower tumor growth rates in treated groups compared to controls, and regulated Pan Kla expression, correlating with decreased cancer cell proliferation	In vitro	[134]
Glycolysis	Fenbendazole (FZ)	Microtubules p53 Hexokinase II	Disruption of microtubule dynamics Increases p53 translocation to mitochondria, which is suggested to induce cell death Inhibition of HK2 activity, leading to apoptosis	FZ administration significantly reduced tumor size and weight in A549 xenografted nude mice	Animal studies	[135]
TCA cycle	Ivosidenib	Isocitrate dehydrogenase 1	Inhibits IDH1 catalysis of the oncometabolite 2HG that disrupts epigenetic regulation, blocks cellular differentiation, and contributes to tumorigenesis	Ivosidenib effectively suppresses plasma 2-HG in IDH1-mutated cholangiocarcinoma and chondrosarcoma, supporting a dose of 500 mg QD for advanced solid tumors	Phase I	[136]
Amino acid synthesis	JPH203 (Nanvuranlat)	L-type Amino Acid Transporter 1	LAT1 inhibition	The drug showed significant improvement in progression-free survival in patients with advanced, refractory biliary tract cancers compared to placebo, with a disease control rate of 25%; the treatment was found to be safe and well tolerated	Phase II	[137,138]
Glycolysis	Marinopyrrole derivative MP1	Myc and mTOR signaling	Modulate global gene expression and inhibit Myc-associated transcriptional targets including translation/mTOR targets. Inhibit tumor growth and Myc expression	MP1 is an orally bioavailable compound with favorable pharmacokinetics and pharmacodynamics, crossing the blood–brain barrier and achieving concentrations above IC50 in tumors, including in the brain, with good tolerability and no significant toxicity	Animal studies	[139,140]
Oxidative phosphorylation	Metformin	NADH	Increased flux of glucose carbons via the pentose phosphate pathway, leading to the inhibition of complex I (NADH:ubiquinone oxidoreductase)	Proneural BTICs respond better to metformin, while mesenchymal BTICs are more glycolytic and less responsive; glycolysis targeting may be more effective for mesenchymal BTICs.	Phase II	[141]
Glycolysis	Dimethylaminomicheliolide (DMAMCL), a Micheliolide derivative	Pyruvate kinase	Covalent binding at residue cysteine424 to promote tetramer formation and selectively activate PKM2	DMAMCL significantly suppresses tumor growth in vivo by activating PKM2, showing potential as a novel anticancer therapeutic drug, with optimal effects observed at 10 μg/mL	Discovery	[142]
Fatty acid synthesis	Omeprazole	Fatty acid synthase (FASN), which is a rate-limiting enzyme in synthesizing fatty acids	Proton pump inhibitors selectively inhibit FASN activity and induce apoptosis in Triple-Negative Breast Cancer (TNBC) cell lines via AKT and HIF-1 under hypoxic stress, allowing for adaptations in the tumor microenvironment	Omeprazole, when added to neoadjuvant AC-T, can safely inhibit FASN and shows a promising pCR rate, though further confirmation is needed	Phase II	[143]
Glycolysis	Oxamate	Lactate Dehydrogenase A	Induces inhibition of LDHA which suppress glucose uptake, lactate secretion, invasion, and proliferation in GH3 cells via the downregulation of GLUT1 and MMP2 expression and the inhibition of the Akt-GSK-3β-cyclinD1 pathway	Oxamate significantly inhibits the invasion and proliferation of primary pituitary PA cells derived from patients after transsphenoidal resection, confirming its potential as a therapeutic agent against human-invasive PA cells	Discovery	[144]
One-carbon metabolism	Methotrexate (MTX), Pemetrexed (PTX)	Serine hydroxymethyltransferases	Inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF (utilized for nucleotide biosynthesis and hyperactivated in cancer)	PTX binds deeper in SHMTs than MTX due to its unique P-moiety structure, making it a more potent inhibitor; polyglutamylation significantly enhances the inhibitory activity of antifolates like PTX and MTX against SHMTs in vivo	Drug repurposing	[145]
Glycolysis	Shikonin	Pyruvate kinase	Decreases the PKM2-mediated aerobic glycolysis switch in tumor cells, thereby inhibiting tumor proliferation	Shikonin suppresses tumor growth in a dose-dependent manner in a mouse model of B16 melanoma at concentrations of 1 mg/kg and 10 mg/kg	Animal studies	[146]
Fatty acid synthesis	TVB 2640 (Denifanstat) + bevacizumab	Fatty acid synthase	Alternation of fatty acid synthase signaling which can drive phenotypic plasticity and cell fate decisions, mitochondrial regulation of cell death, immune escape, and organ-specific metastatic potential	TVB-2640 combined with bevacizumab significantly improved progression-free survival (PFS) in patients with recurrent high-grade astrocytoma compared to historical bevacizumab monotherapy, demonstrating a favorable safety profile and promising efficacy	Phase II	[147]
Amino acid synthesis	Venetoclax with azacitidine	BCL-2	Inhibition of BCL-2 which leads to the suppression of oxidative phosphorylation	Venetoclax and azacitidine show high response rates in treatment-naive patients, but relapsed patients exhibit reduced sensitivity due to metabolic adaptations in leukemic stem cells, indicating potential for targeting fatty acid metabolism	Phase I	[148]

Abbreviations: Hexokinase 2 (HK2); Oxaloacetic acid (OAA); reactive oxygen species (ROS); Monocarboxylate Transporter 1 (MCT1); Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT); Michigan Cancer Foundation-7 (MCF-7); MD Anderson-Metastatic Breast-231 (MDA-MB-231); Histone H3 lysine 9 lactylation (H3K9la); Histone H3 at lysine 56 lactylation (H3K56la); tumor protein 53 (p53); Isocitrate dehydrogenase 1 (IDH1); 2-hydroxyglutarate (2HG); L-type Amino Acid Transporter 1 (LAT1); Myelocytomatosis oncogene (Myc); mechanistic target of rapamycin (mTOR); Nicotinamide Adenine Dinucleotide (NADH); Pyruvate kinase M2 (PKM2); fatty acid synthase (FASN); Lactate Dehydrogenase A (LDHA); Hypoxia-Inducible Factor 1 Subunit Alpha (HIF1); growth hormone (GH3); glucose transporter type 1 (GLUT1); 5;10-methylenetetrahydrofolate (5;10-meTHF); Matrix Metallopeptidase 2 (MMP2); B-cell lymphoma 2 BCL-2 (BCL-2); Anthracycline–Taxane-based Chemotherapy (AC-T); Pathologic Complete Response (pCR); Pituitary Adenoma (PA); Serine Hydroxymethyl Transferase (SHMT); progression-free survival (PFS).