2. Academic Validation
  3. Discovery of 4H-chromeno[2,3-d]pyrimidin-4-one derivatives as senescence inducers and their senescence-associated antiproliferative activities on cancer cells using advanced phenotypic assay

Discovery of 4H-chromeno[2,3-d]pyrimidin-4-one derivatives as senescence inducers and their senescence-associated antiproliferative activities on cancer cells using advanced phenotypic assay

  • Eur J Med Chem. 2021 Jan 1:209:112550. doi: 10.1016/j.ejmech.2020.112550.
Sangmi Oh 1,  Ji Young Lee 2,  Inhee Choi 1,  Arnaud Ogier 3,  Do Yoon Kwon 2,  Hangyeol Jeong 2,  Sook Jin Son 2,  Youngmi Kim 1,  Haejin Kwon 4,  Seijin Park 4,  Hwankyu Kang 4,  Kwanghan Kong 4,  Sujin Ahn 4,  Ulf Nehrbass 2,  Myung Jin Kim 5,  Rita Song 6
Affiliations

Affiliations

  • 1 Medicinal Chemistry Group, Institut Pasteur Korea, 16 Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea.
  • 2 Functional Morphometry-I, Institut Pasteur Korea, 16 Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea.
  • 3 Cellular Differentiation and Toxicity Prediction, Institut Pasteur Korea, 16 Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea.
  • 4 Drug Metabolism and Pharmacokinetics, Institut Pasteur Korea, 16 Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea.
  • 5 Functional Morphometry-I, Institut Pasteur Korea, 16 Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea. Electronic address: nanmolra1973@naver.com.
  • 6 Medicinal Chemistry Group, Institut Pasteur Korea, 16 Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, South Korea. Electronic address: rsong1228@gmail.com.
PMID: 33268144 DOI: 10.1016/j.ejmech.2020.112550
Abstract

Current research suggests therapy-induced senescence (TIS) of Cancer cells characterized by distinct morphological and biochemical phenotypic changes represent a novel functional target that may enhance the effectiveness of Cancer therapy. In order to identify novel small-molecule inducers of cellular senescence and determine the potential to be used for the treatment of melanoma, a new method of high-throughput screening (HTS) and high-contents screening (HCS) based on the detection of morphological changes was designed. This image-based and whole cell-based technology was applied to screen and select a novel class of antiproliferative agents on Cancer cells, 4H-chromeno[2,3-d]pyrimidin-4-one derivatives, which induced senescence-like phenotypic changes in human melanoma A375 cells without serious cytotoxicity against normal cells. To evaluate structure-activity relationship (SAR) study of 4H-chromeno[2,3-d]pyrimidin-4-one scaffold starting from hit 3, a focused library containing diversely modified analogues was constructed and which led to the identification of 38, a novel compound to have remarkable anti-melanoma activity in vitro with good metabolic stability.

Keywords

Antiproliferative agents; High-contents screening; High-throughput screening; Melanoma; Senescence; Structure-activity relationship.

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