2. Academic Validation
  3. Discovery of pyrido[3,2-d]pyrimidin-6(5H)-one derivatives as checkpoint kinase 1 (CHK1) inhibitors with potent antitumor efficacy

Discovery of pyrido[3,2-d]pyrimidin-6(5H)-one derivatives as checkpoint kinase 1 (CHK1) inhibitors with potent antitumor efficacy

  • Eur J Med Chem. 2024 Apr 5:269:116351. doi: 10.1016/j.ejmech.2024.116351.
Shihe Hu 1,  Cuihua Jiang 2,  Qiaomei Jin 3
Affiliations

Affiliations

  • 1 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China; SkyRun Pharma Co., Ltd., No. 9 Weidi Road, Nanjing, 210046, China.
  • 2 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
  • 3 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China. Electronic address: [email protected].
PMID: 38547734 DOI: 10.1016/j.ejmech.2024.116351
Abstract

Checkpoint kinase 1 (Chk1) plays a crucial role in the DNA damage response pathway, making it an attractive target for Cancer therapy. Herein, we present the synthesis, optimization, and evaluation of selective Chk1 inhibitors with a pyrido[3,2-d]pyrimidin-6(5H)-one scaffold. Among them, compound 11 showed single-digit nanomolar potency against Chk1 (IC50: 0.55 nM) with good kinase selectivity. Notably, 11 showed anti-proliferative effect in MV-4-11 cells singly (IC50 = 202 nM) and a synergistic effect in combination with gemcitabine in HT-29 cells (IC50 = 63.53 nM). Furthermore, the combination of 11 and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Overall, this work provides a strong foundation for the development of selective Chk1 inhibitors and the therapeutic strategy for Cancer.

Keywords

Biological evaluation; Checkpoint kinase 1 (CHK1); Kinase inhibitor; Pyrido[3,2-d]pyrimidin-6(5H)-one; Synthesis.

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