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tid Target Cancers General Effect on Target
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Warburg Effect

The Warburg effect (aerobic glycolysis) is a metabolic phenotype where many cancer cells use high glycolytic flux and lactate production even when oxygen is available. Tumors often contain hypoxic regions that further drive glycolysis, but Warburg metabolism can also occur under normoxic conditions (“pseudo-hypoxia”) via oncogenic signaling and metabolic rewiring.

Hypoxia-inducible factor 1 alpha (HIF-1α) is one important driver in hypoxic tumor regions. HIF-1α upregulates glycolytic genes (e.g., GLUT1, HK2, LDHA) and promotes reduced mitochondrial pyruvate oxidation in part through induction of PDK (which inhibits PDH), shifting carbon toward lactate.

Warburg effect (GLUT1, LDHA, HK2, and PKM2).
Classic HIF-Warburg axis: PDK1 and MCT4 (SLC16A3) (pyruvate gate + lactate export).

Here are some of the key pathways and potential targets:

Note: use database Filter to find inhibitors: Ex pick target HIF1α, and effect direction ↓

1.Glycolysis Inhibitors:(2-DG, 3-BP)
- HK2 Inhibitors: such as 2-deoxyglucose, can reduce glycolysis
-PFK1 Inhibitors: such as PFK-158, can reduce glycolysis
-PFKFB Inhibitors:
- PKM2 Inhibitors: (Shikonin)
-Can reduce glycolysis
- LDH Inhibitors: (Gossypol, FX11)
-Reducing the conversion of pyruvate to lactate.
-Inhibiting the production of ATP and NADH.
- GLUT1 Inhibitors: (phloretin, WZB117)
-A key transporter involved in glucose uptake.
-GLUT3 Inhibitors:
- PDK1 Inhibitors: (dichloroacetate)
- A key enzyme involved in the regulation of glycolysis. PDK inhibitors (e.g., DCA) activate PDH and shift pyruvate into TCA/OXPHOS, reducing lactate pressure.

2.Pentose phosphate pathway:
- G6PD Inhibitors: can reduce the pentose phosphate pathway

3.Hypoxia-inducible factor 1 alpha (HIF1α) pathway:
- HIF1α inhibitors: (PX-478,Shikonin)
-Reduce expression of glycolytic genes and inhibit cancer cell growth.

4.AMP-activated protein kinase (AMPK) pathway:
-AMPK activators: (metformin,AICAR,berberine)
-Can increase AMPK activity and inhibit cancer cell growth.

5.mTOR pathway:
- mTOR inhibitors:(rapamycin,everolimus)
-Can reduce mTOR activity and inhibit cancer cell growth.

Warburg Targeting Matrix (Cancer Metabolism)

Node What It Does (Warburg role) Representative Inhibitors / Modulators Mechanism Snapshot Typical Tumor Effects Best-Fit Tumor Context Common Constraints / Gotchas TSF Combination Logic
GLUT (glucose uptake)
GLUT1 (SLC2A1) focus		 Controls glucose entry; sets the upper bound on glycolytic flux. Research/repurposing: WZB117 (GLUT1), BAY-876 (GLUT1), STF-31 (GLUT1 tool), Fasentin (GLUT), Phloretin (broad, weak)
Dietary/indirect: some polyphenols reported to lower GLUT1 expression (context) 		Blocks glucose transport or reduces GLUT1 expression → less substrate for glycolysis & PPP. ATP stress (in highly glycolytic tumors), lactate ↓, growth slowdown; can sensitize to stressors. High-GLUT1 tumors; hypoxic / glycolysis-addicted phenotypes. Systemic glucose handling and glucose-dependent tissues; tumor compensation via alternate fuels. P, R Pairs with ROS/ETC stressors or LDH/MCT blockade; beware compensatory glutaminolysis/fatty acid oxidation.
Hexokinase (HK2)
first committed glycolysis step		 Traps glucose as G-6-P; HK2 often upregulated and mitochondria-associated in tumors. Clinical/adjunct interest: 2-Deoxyglucose (2-DG; glycolysis + glycosylation stress)
Research: Lonidamine-class glycolysis axis drugs (not “pure HK2”), 3-bromopyruvate (hazardous research agent; not for casual use) 		Competitive substrate mimic (2-DG) → 2-DG-6P accumulation; HK flux ↓; ER glycosylation stress ↑. ATP ↓, AMPK ↑, ER stress/UPR ↑, autophagy ↑, apoptosis (context); radiosensitization reported. Highly glycolytic tumors; tumors with strong HK2 dependence; hypoxic cores. Normal glucose-dependent tissues; ER-stress toxicities; dosing/tolerability limits in practice. P, R, G Pairs with radiation, pro-oxidant stress, or MCT/LDH blockade; watch systemic glucose effects.
LDH (LDHA/LDHB)
pyruvate ⇄ lactate		 Regenerates NAD+ to sustain glycolysis; LDHA supports lactate production and acidification. Tier A direct inhibitors: FX11, (R)-GNE-140, NCI-006, Oxamate, Galloflavin, Gossypol
Tier B indirect: polyphenols (often lactate/LDH expression ↓ rather than catalytic inhibition) 		Blocks LDH catalysis → NAD+ recycling ↓ → glycolysis throttles; pyruvate handling shifts; redox pressure ↑. Lactate ↓, glycolytic flux ↓, oxidative stress ↑ (often secondary), growth inhibition; immune microenvironment may improve if lactate decreases. LDHA-high tumors; lactate-driven immunosuppression; glycolysis-addicted phenotypes. Metabolic plasticity: tumors switch fuels; some LDH inhibitors have PK liabilities; “LDH release” ≠ LDH inhibition. R, G Pairs with MCT inhibition (trap lactate), NAD+ axis inhibitors, immune therapy (lactate suppression logic), and OXPHOS stressors (context).
MCT (lactate transport)
MCT1 (SLC16A1), MCT4 (SLC16A3)		 Exports lactate + H+ (acidifies TME); enables lactate shuttling between tumor subclones. Clinical-stage: AZD3965 (MCT1 inhibitor; clinical trials)
Research: AR-C155858 (MCT1/2), Syrosingopine (MCT1/4; repurposed), Lonidamine (MCT + MPC axis) 		Blocks lactate export/import → intracellular acid stress ↑ (in glycolytic cells) and lactate shuttling ↓. Acid stress, growth inhibition; may improve immune function by reducing lactate/acidic suppression (context). MCT1-high tumors; oxidative “lactate-using” tumor fractions; tumors with lactate shuttling. MCT4-driven export can bypass MCT1-only inhibitors; hypoxia upregulates MCT4; need target matching. P, R Pairs strongly with LDH inhibitors (cut production + block export), and with immune therapy rationale (lactate/acid microenvironment).
PDK (PDK1-4)
PDH gatekeeper		 PDK inhibits PDH → keeps pyruvate out of mitochondria; supports Warburg by favoring lactate. Prototype: Dichloroacetate (DCA; pan-PDK inhibitor “classic”)
Research: AZD7545 (PDK2 inhibitor; tool), newer PDK inhibitor series (research) 		Inhibits PDK → PDH active ↑ → pyruvate into TCA/OXPHOS ↑; lactate pressure ↓. Warburg reversal pressure (context), lactate ↓, mitochondrial flux ↑; can increase ROS in some settings (secondary). PDK-high tumors; tumors with suppressed PDH flux; “glycolysis locked” metabolic phenotype. Requires functional mitochondrial capacity; hypoxia can limit OXPHOS shift; effect is often modulatory rather than directly cytotoxic. R, G Pairs with therapies that exploit mitochondrial dependence or redox stress; can complement LDH/MCT strategies by reducing lactate drive.

Time-Scale Flag (TSF): P / R / G





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