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Updated: Jun 18, 2025

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
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Cheminformatics-based identification of phosphorylated RET tyrosine kinase inhibitors for human cancer

Md Enamul Kabir Talukder1,2, Md Aktaruzzaman1,3, Noimul Hasan Siddiquee1,4

  • 1Laboratory of Computational Biology, Biological Solution Centre, Jashore, Bangladesh.

Frontiers in Chemistry
|August 1, 2024
PubMed
Abstract

Insights

Researchers identified four novel compounds targeting the rearranged during transfection (RET) oncogene, a key driver in multiple cancers. These compounds show potential for inhibiting RET tyrosine kinase activity and could lead to new cancer treatments.

Area of Science:

  • Oncology
  • Computational Chemistry
  • Drug Discovery

Background:

  • The rearranged during transfection (RET) oncogene plays a critical role in the development and progression of various cancers, including lung, thyroid, pancreatic, breast, and colorectal cancers.
  • Dysregulation of RET signaling is a significant factor in tumorigenesis, underscoring the need for targeted therapeutic strategies.
  • Identifying novel compounds that can effectively inhibit RET activity is crucial for developing new cancer treatments.

Purpose of the Study:

  • To discover and evaluate potential lead compounds that target the RET oncogene.
  • To assess the efficacy of these compounds in inhibiting cancer progression across different cancer types.

Main Methods:

  • Utilized high-throughput virtual screening (HTVS) of the ZINC database to identify initial compound candidates.
  • Employed molecular docking and MM-GBSA solvation to assess binding affinities and predict compound stability.
  • Conducted molecular dynamics (MD) simulations to further validate the stability of promising compounds with target receptors.

Main Results:

  • HTVS identified 2,550 potential compounds from over 170,000.
  • Molecular docking studies pinpointed 10 compounds with favorable binding scores.
  • MM-GBSA and MD simulations confirmed the stability and potential inhibitory activity of four specific compounds (CID 95842900, CID 137030374, CID 124958150, CID 110126793).

Conclusions:

  • The four identified compounds demonstrate potential for inhibiting phosphorylated RET (pRET) tyrosine kinase activity.
  • These compounds represent promising candidates for the development of novel therapeutic agents against RET-driven cancers.
  • Further research is warranted to explore the clinical application of these compounds in cancer treatment.
Keywords:
cancerdocking validationextra precision dockinghigh-throughput virtual screeningmolecular dynamics simulationmolecular mechanics with generalized Born surface areaphase databasephosphorylated rearranged during transfection tyrosine kinase

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