Description: <b>3BP</b>, a small molecule, results in a remarkable therapeutic effect when it comes to treating cancers exhibiting a <a href="https://pubmed.ncbi.nlm.nih.gov/22382780/">"Warburg effect."</a> <br>
<p><b>3-Bromopyruvate</b> — also written as <b>3BP</b> or <b>3-BrPA</b> — is a small, highly electrophilic <i>pyruvate/lactate analog</i> that acts as a metabolism-targeting <i>alkylating agent</i> (covalently modifying protein thiols) and is widely studied as an experimental anticancer compound. Functionally, it is best classified as a <b>metabolic poison / anti-metabolite</b> with multi-target effects centered on rapid ATP collapse (glycolysis + mitochondrial metabolism) and secondary oxidative and cell-death signaling. Cancer selectivity is often framed as higher uptake via <b>MCT1</b> and higher reliance on glycolysis/Warburg metabolism, but the same chemical reactivity underlies a narrow safety margin unless formulated/delivered carefully.</p>
<p><b>Primary mechanisms (ranked):</b></p>
<ol>
<li>Covalent thiol alkylation of energy-metabolism enzymes (notably glycolytic nodes such as HK2 and other thiol-sensitive enzymes) → rapid ATP depletion</li>
<li>Mitochondrial bioenergetic disruption (OXPHOS inhibition, permeability/ΔΨm collapse) → energetic crisis</li>
<li>MCT1-facilitated uptake (context-dependent determinant of sensitivity and “selectivity”)</li>
<li>Oxidative stress induction and redox-buffer depletion (ROS↑; GSH/thiols↓) (secondary but often decisive)</li>
<li>Stress-response execution programs (AMPK activation; apoptosis/autophagy; ferroptosis context-dependent; sensitization to other therapies)</li>
</ol>
<p><b>Bioavailability / PK relevance:</b> Unformulated 3BP is chemically reactive and can be systemically toxic; practical translation has focused on formulation (e.g., cyclodextrin/microencapsulation) and/or locoregional delivery to improve tolerability and tumor exposure. Uptake can depend on transporter context (e.g., MCT1 expression) and extracellular pH/lactate milieu (context-dependent).</p>
<p><b>In-vitro vs systemic exposure relevance:</b> Many in-vitro studies use µM–mM ranges; higher (mM) conditions may exceed what is plausibly achievable systemically without toxicity. Reported activity at low µM exists in some models (especially with optimized derivatives/formulations), but exposure/target-engagement in humans remains the central constraint.</p>
<p><b>Clinical evidence status:</b> <b>Not an approved drug</b>. Evidence is predominantly preclinical (cell/animal). Human use has been limited and controversial, including safety incidents reported in non-standard clinical settings. A <b>3BP-derived clinical agent</b> (e.g., KAT/3BP / KAT-101) is in early-phase clinical testing (HCC), but that is distinct from generic/unformulated 3BP.</p>
Overall, 3BP attacks cancer cells by “starving” them of energy, leading to energetic collapse, oxidative damage, and eventual cell death. <br>
<br>
- 3BP is known to inhibit enzymes involved in glycolysis, such as hexokinase II (HKII). Many cancer cells overexpress HKII and rely on glycolysis for ATP production. Inhibiting HKII leads to decreased ATP levels and energy depletion.<br>
- Fermentation inhibitor:(inhibits conversion of pyruvate to lactate) NAD+ is compromised slowing Glycolysis leading to reduced ATP<br>
- By depleting ATP, 3BP can impair mitochondrial functions indirectly.<br>
- LDH converts pyruvate to lactate. In many cancers, lactate production is high (the Warburg effect). Inhibition of LDH disrupts lactate production and may contribute to an intracellular buildup of toxic metabolites.<br>
- There is evidence indicating that, by interfering with glycolysis, 3BP might also indirectly affect the PPP. This reduces the production of NADPH, weakening the cancer cell’s ability to manage oxidative stress.<br>
- Impairing energy metabolism, 3BP can indirectly affect mitochondrial function, potentially leading to an increase in ROS production. <br>
<br>
Although 3BP shows promise as a metabolic inhibitor with anticancer properties, its transition from preclinical studies to approved clinical therapy has not yet been realized. <br>
<br>
-Combining metabolic inhibitors like 3BP with agents that modulate ROS levels could represent a synergistic approach in cancer therapy. By simultaneously disrupting energy production and exacerbating oxidative stress, such combinations may more effectively induce cancer cell death while sparing normal cells.<br>
<br>
In advanced cancer it has been known to kill the cancer too fast, causing liver failure and death.<br>
<br>
<h3>3-Bromopyruvate (3BP, 3-BrPA) — mechanistic axes (oncology)</h3>
<table>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Glycolysis inhibition via thiol-alkylation of glycolytic enzymes</td>
<td>↓ glycolytic flux; ↓ ATP (often rapid)</td>
<td>↔ to ↓ (model-dependent)</td>
<td>P/R</td>
<td>Energetic collapse</td>
<td>Often framed around HK2, but 3BP is broadly thiol-reactive; glycolysis collapse is a convergent phenotype rather than a single-enzyme story.</td>
</tr>
<tr>
<td>2</td>
<td>Mitochondrial bioenergetics disruption</td>
<td>↓ OXPHOS; ↓ ΔΨm; ↑ MPTP (context-dependent)</td>
<td>↔ to ↓ (dose-dependent)</td>
<td>P/R</td>
<td>ATP depletion + mitochondrial stress</td>
<td>Dual hit (glycolysis + mitochondria) is a major reason for potency in high-glycolytic tumors; also a toxicity driver if exposure is systemic.</td>
</tr>
<tr>
<td>3</td>
<td>MCT1-dependent uptake</td>
<td>↑ uptake and sensitivity when MCT1-high</td>
<td>↔ (varies by tissue MCT1)</td>
<td>P</td>
<td>Determinant of selectivity</td>
<td>MCT1 has been shown as a key sensitivity node in multiple models; “selectivity” claims are strongest when transporter context is documented.</td>
</tr>
<tr>
<td>4</td>
<td>Redox buffering and thiol pool depletion</td>
<td>↓ GSH/thiols; redox crisis</td>
<td>↔ to ↓ (dose-dependent)</td>
<td>R/G</td>
<td>Lowered antioxidant capacity</td>
<td>Because 3BP alkylates thiols, GSH depletion can be both direct and indirect; can amplify downstream death pathways and resistance phenotypes.</td>
</tr>
<tr>
<td>5</td>
<td>ROS axis</td>
<td>↑ ROS (often); oxidative damage (context-dependent)</td>
<td>↔ (dose- and context-dependent)</td>
<td>R</td>
<td>Oxidative stress amplification</td>
<td>ROS changes are frequently secondary to mitochondrial disruption + thiol depletion; can be decisive for apoptosis/ferroptosis engagement.</td>
</tr>
<tr>
<td>6</td>
<td>AMPK energy-stress signaling</td>
<td>↑ AMPK; ↓ anabolic signaling (context-dependent)</td>
<td>↑ AMPK (protective or adaptive)</td>
<td>R</td>
<td>Stress adaptation vs death priming</td>
<td>Energetic collapse typically triggers AMPK; downstream outcomes depend on baseline metabolic state and co-treatments.</td>
</tr>
<tr>
<td>7</td>
<td>Cell-death programs: apoptosis and autophagy</td>
<td>↑ apoptosis; ↑ autophagy (context-dependent)</td>
<td>↔ to ↑ stress responses</td>
<td>G</td>
<td>Execution of cytotoxicity</td>
<td>Multiple reports show mixed death phenotypes; autophagy can be cytoprotective or contribute to death depending on context and timing.</td>
</tr>
<tr>
<td>8</td>
<td>Ferroptosis axis</td>
<td>↑ ferroptosis susceptibility (context-dependent)</td>
<td>↔ (context-dependent)</td>
<td>G</td>
<td>Lipid-peroxidation-driven death</td>
<td>Most consistent when redox buffering is weakened and/or combined with agents that tilt iron/lipid-ROS balance.</td>
</tr>
<tr>
<td>9</td>
<td>NRF2 axis</td>
<td>↔ (model-dependent; often stress-activated)</td>
<td>↔ (model-dependent)</td>
<td>G</td>
<td>Adaptive antioxidant response</td>
<td>NRF2 behavior varies: oxidative stress can activate NRF2, but thiol-alkylation/redox collapse can also overwhelm defenses; treat as context-dependent.</td>
</tr>
<tr>
<td>10</td>
<td>Chemosensitization / radiosensitization</td>
<td>↑ sensitization (context-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Combination leverage</td>
<td>Reported synergy with targeted therapy/chemo/radiation in some models, typically via metabolic stress + redox imbalance.</td>
</tr>
<tr>
<td>11</td>
<td>Clinical Translation Constraint</td>
<td>Formulation/delivery-limited; systemic toxicity risk</td>
<td>Off-target injury risk</td>
<td>—</td>
<td>Therapeutic index limitation</td>
<td>Unformulated 3BP has significant toxicity concerns; translation efforts emphasize formulation (e.g., cyclodextrin/microencapsulation) and/or locoregional strategies and derivatives now entering early clinical trials.</td>
</tr>
</table>