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

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

  • Bioorg Med Chem Lett. 2024 Feb 3:129645. doi: 10.1016/j.bmcl.2024.129645.
Su Hyun Ji 1,  Han Byeol Kim 1,  Yeonju Song 2,  Hwan Won Chung 3,  Duck-Hyung Lee 4,  Cheulhee Jung 5,  Yeonjin Ko 6,  Seo-Jung Han 7
Affiliations

Affiliations

  • 1 Chemical & 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.
  • 2 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 3 Computational Science Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 4 Department of Chemistry, Sogang University, 35 Baekbeom Ro, Seoul 04107, Republic of Korea.
  • 5 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 6 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea. Electronic address: yko@kist.re.kr.
  • 7 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: sjhan@kist.re.kr.
PMID: 38316368 DOI: 10.1016/j.bmcl.2024.129645
Abstract

Lymphocyte-Specific Protein Tyrosine Kinase (Lck) plays vital roles in the T-cell receptor- mediated development, function, and differentiation of T-cells. Given its substantial involvement in T cell signaling, irregularities in the expression and functionality of Lck may lead to various diseases, including Cancer. In this study, we found that compound 12a exerted significant inhibitory potency against Lck with an IC50 value of 10.6 nM. In addition, 12a demonstrated high efficacy in various colon Cancer cell lines as indicated by GI50 values ranging from 0.24-1.26 μM. Notably, 12a inhibited the phosphorylation of Lck in Colo201 cells. Overall, the anti-proliferative effects of 12a on diverse Cancer cell lines highlights its potential application for the treatment of various Cancer types.

Keywords

Cancer; Colon cancer; Drug design; Kinase; Lck.

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