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Updated: Jul 4, 2025

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Identification of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffolds as potent Lck inhibitors as anti-cancer

Su Hyun Ji1, Han Byeol Kim1, Yeonju Song2

  • 1Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemistry, Sogang University, 35 Baekbeom Ro, Seoul 04107, Republic of Korea.

Bioorganic & Medicinal Chemistry Letters
|February 5, 2024
PubMed

Insights

Compound 12a significantly inhibits Lymphocyte-specific protein tyrosine kinase (Lck), a key T-cell regulator. This compound shows potent anti-cancer effects in colon cancer cell lines, indicating its therapeutic potential.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Lymphocyte-specific protein tyrosine kinase (Lck) is crucial for T-cell receptor signaling, impacting T-cell development and function.
  • Dysregulation of Lck is implicated in the pathogenesis of various diseases, notably cancer.

Purpose of the Study:

  • To investigate the inhibitory potential of compound 12a against Lck.
  • To evaluate the anti-proliferative efficacy of compound 12a in colon cancer cell lines.

Main Methods:

  • In vitro kinase inhibition assays to determine IC50 values for Lck inhibition.
  • Cell viability assays (GI50) across multiple colon cancer cell lines.
  • Western blot analysis to assess Lck phosphorylation inhibition in cancer cells.

Main Results:

  • Compound 12a demonstrated potent inhibition of Lck with an IC50 of 10.6 nM.
  • 12a exhibited significant anti-proliferative activity against colon cancer cell lines, with GI50 values between 0.24 and 1.26 μM.
  • 12a effectively inhibited Lck phosphorylation in Colo201 cells.

Conclusions:

  • Compound 12a is a potent Lck inhibitor.
  • The anti-proliferative effects of 12a in colon cancer cells suggest its potential as a therapeutic agent for various cancers.
Keywords:
CancerColon cancerDrug designKinaseLck

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