2. Academic Validation
  3. Tepotinib interaction triggers a slight effect on the overall stability of hemoglobin protein, reinforcing the potential suitability as a drug candidate against gastric cancer

Tepotinib interaction triggers a slight effect on the overall stability of hemoglobin protein, reinforcing the potential suitability as a drug candidate against gastric cancer

  • Int J Biol Macromol. 2025 Jun;311(Pt 1):143133. doi: 10.1016/j.ijbiomac.2025.143133.
Donghao Wu 1,  Zexiao Lin 2,  Jingyun Wen 3,  Xiangyuan Wu 4
Affiliations

Affiliations

  • 1 Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: wudh5@mail.sysu.edu.cn.
  • 2 Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: linzxiao@mail.sysu.edu.cn.
  • 3 Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: wenjingy@mail.sysu.edu.cn.
  • 4 Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: wuxiangy@mail.sysu.edu.cn.
PMID: 40228765 DOI: 10.1016/j.ijbiomac.2025.143133
Abstract

The interaction of Anticancer agents with blood proteins can significantly impact their pharmacokinetics and pharmacodynamics. This study investigates the interaction of tepotinib, a Met Inhibitor, with human Hemoglobin (Hb) and its Anticancer effects on SNU-620 gastric Cancer (GC) cells. UV-visible spectroscopy revealed a slight reduction in Hb stability upon tepotinib binding, with a decrease in melting temperature (Tm) from 62 °C to 60 °C. Circular dichroism (CD) analysis showed a minor decrease in Hb's α-helical content, while fluorescence spectroscopy confirmed a strong binding affinity with spontaneous and exothermic interaction. Molecular docking identified Trp 37 at the α1β2 interface as the primary binding site, stabilized by Arg 141, Thr 137, Lys 127, and Ser 131 through hydrogen bonding. Molecular dynamics simulations (200 ns) confirmed the stability of the Hb-tepotinib complex. Cellular assays demonstrated that tepotinib effectively inhibited SNU-620 GC cell proliferation (IC50 = 10 nM) by promoting Apoptosis, with Caspase-3 upregulation and anti-apoptotic protein downregulation. Since drug-protein interactions play a crucial role in drug bioavailability, stability, and therapeutic efficacy, understanding these interactions is essential for optimizing tepotinib's clinical application.

Keywords

Gastric cancer; Hemoglobin interaction; Tepotinib.

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