tbResList Print — SRF Sorafenib (brand name Nexavar)

Features: kinase inhibitor drug

Description: <p><b>Sorafenib</b> (brand: <b>Nexavar</b>) — an oral multikinase inhibitor targeting RAF kinases and multiple receptor tyrosine kinases (VEGFR-1/2/3, PDGFR-β, FLT3, KIT, RET). Approved for advanced hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and differentiated thyroid carcinoma (DTC).</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) RAF (CRAF/BRAF) inhibition → ↓ MAPK/ERK signaling<br>
2) VEGFR/PDGFR blockade → anti-angiogenesis<br>
3) Induction of mitochondrial apoptosis (Mcl-1↓; caspases↑)<br>
4) Metabolic/redox stress modulation (ROS shifts; ferroptosis sensitization reported)<br>
5) Tumor microenvironment effects (vascular normalization / hypoxia interplay)</p>
<p><b>Bioavailability / PK relevance:</b> Oral; variable absorption; highly protein-bound; metabolized mainly by CYP3A4 and UGT1A9; half-life ~25–48 h. Achievable plasma levels are within low-micromolar range.</p>
<p><b>In-vitro vs oral exposure:</b> Many mechanistic studies use concentrations within or slightly above clinical plasma range; off-target cytotoxicity typically at higher doses.</p>
<p><b>Clinical evidence status:</b> FDA-approved for HCC, RCC, DTC; established survival benefit in advanced disease (modest median OS improvement).</p>


<b>Inhibitors</b> of vascular endothelial growth factor receptor (VEGFR); used to treat kidney, liver and thyroid cancers.<br>


<br>
<h3>Sorafenib (Nexavar) — Cancer vs Normal Cell Pathway Map</h3>
<table border="1" cellpadding="4" cellspacing="0">
<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>RAF → MEK → ERK (MAPK)</td>
<td>↓ (primary)</td>
<td>↔ / ↓ (proliferating cells)</td>
<td>R/G</td>
<td>Reduced proliferative signaling</td>
<td>Core intracellular target; inhibits CRAF and wild-type BRAF (not selective for BRAF V600E like vemurafenib).</td>
</tr>

<tr>
<td>2</td>
<td>VEGFR / PDGFR (angiogenesis)</td>
<td>↓ tumor vascularization</td>
<td>↓ endothelial proliferation</td>
<td>R/G</td>
<td>Anti-angiogenic effect</td>
<td>Major driver of clinical efficacy in HCC/RCC; affects tumor microenvironment.</td>
</tr>

<tr>
<td>3</td>
<td>Intrinsic apoptosis (Mcl-1↓, caspases↑)</td>
<td>↑</td>
<td>↔ / ↑ (dose-dependent)</td>
<td>R/G</td>
<td>Mitochondrial apoptosis</td>
<td>Mcl-1 downregulation is characteristic; enhances chemosensitivity in some models.</td>
</tr>

<tr>
<td>4</td>
<td>ROS</td>
<td>↑ (dose-dependent)</td>
<td>↔ / ↑ (high exposure)</td>
<td>P/R</td>
<td>Oxidative stress contribution</td>
<td>Redox stress may contribute to cytotoxicity and resistance mechanisms.</td>
</tr>

<tr>
<td>5</td>
<td>Ferroptosis</td>
<td>↑ (context-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Lipid peroxidation vulnerability</td>
<td>Reported to sensitize HCC cells to ferroptosis via system Xc⁻ / SLC7A11 modulation.</td>
</tr>

<tr>
<td>6</td>
<td>PI3K/AKT/mTOR</td>
<td>↓ (secondary; model-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Reduced survival signaling</td>
<td>Often compensatory pathway in resistance; combination target in trials.</td>
</tr>

<tr>
<td>7</td>
<td>HIF-1α</td>
<td>↓ (anti-angiogenic coupling)</td>
<td>↔</td>
<td>G</td>
<td>Reduced hypoxia signaling</td>
<td>Indirect via vascular effects; hypoxia may paradoxically increase in resistant tumors.</td>
</tr>

<tr>
<td>8</td>
<td>NRF2</td>
<td>↑ (resistance-associated; context-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Adaptive antioxidant response</td>
<td>NRF2 upregulation linked to sorafenib resistance in HCC.</td>
</tr>

<tr>
<td>9</td>
<td>Ca²⁺ signaling</td>
<td>↔ (stress-related)</td>
<td>↔</td>
<td>P/R</td>
<td>Not primary axis</td>
<td>Secondary to mitochondrial stress; not direct target.</td>
</tr>

<tr>
<td>10</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>↓ (toxicity)</td>
<td>—</td>
<td>Resistance + tolerability limits</td>
<td>Common AEs: hand-foot skin reaction, hypertension, diarrhea; resistance frequent via MAPK reactivation or NRF2 upshift.</td>
</tr>

</table>

<p><b>TSF legend:</b><br>
P: 0–30 min (kinase inhibition onset)<br>
R: 30 min–3 hr (signaling cascade suppression)<br>
G: &gt;3 hr (gene regulation, angiogenesis suppression, apoptosis)</p>