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

Hao-Yue Xiang; Xiang Wang; Yan-Hong Chen; Xi Zhang; Cun Tan; Yi Wang; Yi Su; Zhi-Wei Gao; Xiao-Yan Chen; Bing Xiong; Zhao-Bing Gao; Yi Chen; Jian Ding; Ling-Hua Meng; Chun-Hao Yang

doi:10.1016/j.ejmech.2020.112913

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. Epub 2020 Oct 21.

Authors

Hao-Yue Xiang¹, Xiang Wang², Yan-Hong Chen³, Xi Zhang², Cun Tan³, Yi Wang², Yi Su², Zhi-Wei Gao⁴, Xiao-Yan Chen⁴, Bing Xiong³, Zhao-Bing Gao⁵, Yi Chen², Jian Ding⁶, Ling-Hua Meng⁷, Chun-Hao Yang⁸

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.

MeSH terms

Angiogenesis Inhibitors / chemical synthesis*
Angiogenesis Inhibitors / pharmacology
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Drug Screening Assays, Antitumor
Female
Humans
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Targeted Therapy
Morpholines / chemical synthesis*
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis*
Phosphoinositide-3 Kinase Inhibitors / pharmacology
Phosphorylation / drug effects
Piperazines / chemical synthesis*
Piperazines / pharmacology
Protein Binding
Proto-Oncogene Proteins c-akt / metabolism
Pyrroles / chemical synthesis*
Pyrroles / pharmacology
Structure-Activity Relationship
TOR Serine-Threonine Kinases / metabolism

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
CYH33
Morpholines
Phosphoinositide-3 Kinase Inhibitors
Piperazines
Pyrroles
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases