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: jding@simm.ac.cn.
7 Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: lhmeng@simm.ac.cn.
8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: chyang@simm.ac.cn.

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.

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