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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.
- Source :
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European journal of medicinal chemistry [Eur J Med Chem] 2021 Jan 01; Vol. 209, pp. 112913. Date of Electronic Publication: 2020 Oct 21. - Publication Year :
- 2021
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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 (IC <subscript>50</subscript>  = 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Angiogenesis Inhibitors pharmacology
Animals
Antineoplastic Agents pharmacology
Drug Screening Assays, Antitumor
Female
Humans
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Targeted Therapy
Morpholines pharmacology
Phosphoinositide-3 Kinase Inhibitors pharmacology
Phosphorylation drug effects
Piperazines pharmacology
Protein Binding
Proto-Oncogene Proteins c-akt metabolism
Pyrroles pharmacology
Structure-Activity Relationship
TOR Serine-Threonine Kinases metabolism
Mice
Angiogenesis Inhibitors chemical synthesis
Antineoplastic Agents chemical synthesis
Morpholines chemical synthesis
Phosphatidylinositol 3-Kinases metabolism
Phosphoinositide-3 Kinase Inhibitors chemical synthesis
Piperazines chemical synthesis
Pyrroles chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 209
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33109399
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112913