Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors

  • Eur J Med Chem. 2021 Jan 1:209:112913. doi: 10.1016/j.ejmech.2020.112913.
Hao-Yue Xiang  1 ,  Xiang Wang  2 ,  Yan-Hong Chen  3 ,  Xi Zhang  2 ,  Cun Tan  3 ,  Yi Wang  2 ,  Yi Su  2 ,  Zhi-Wei Gao  4 ,  Xiao-Yan Chen  4 ,  Bing Xiong  3 ,  Zhao-Bing Gao  5 ,  Yi Chen  2 ,  Jian Ding  6 ,  Ling-Hua Meng  7 ,  Chun-Hao Yang  8
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China.
  • 2. Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 4. Center for Drug Metabolism Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 5. Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 6. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Shanghai HaiHe Pharmaceutical Co. Ltd., Shanghai, 201203, PR China. Electronic address: [email protected].
  • 7. Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: [email protected].
  • 8. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: [email protected].
PMID: 33109399 DOI: 10.1016/j.ejmech.2020.112913
Abstract

In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential Anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα Inhibitor (IC50 = 5.9 nM, β/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of Akt in human Cancer cells to modulate the cellular PI3K/Akt/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved.

Keywords
Anti-cancer; PI3K; Pyrrolo[2,1-f][1,2,4]triazine; Target therapy.