Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Álvarez, RM; García, AB; Riesco-Fagundo, C; Martín, JI; Varela, C; Rodríguez, Hergueta, A; González, Cantalapiedra, E; Oyarzabal, J; Di, Geronimo, B; Lorenzo, M; Albarrán, MI; Cebriá, A; Cebrián, D; Martínez-González, S; Blanco-Aparicio, C; Pastor, J.
Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors.
Eur J Med Chem. 2021; 211: 113109
Doi: 10.1016/j.ejmech.2020.113109
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Di Geronimo Quintero Bruno
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- Abstract:
- Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells. Compounds targeting this pathway are under active development as anticancer therapeutics and some of them have reached advanced clinical trials or been approved by the FDA. Dual PI3K/mTOR inhibitors combine multiple therapeutic efficacies in a single molecule by inhibiting the pathway both upstream and downstream of AKT. Herein, we report our efforts on the exploration of novel small molecule macrocycles (MCXs) as dual PI3K/mTOR inhibitors. Macrocyclization is an attractive approach used in drug discovery, as the semi-rigid character of these structures could provide improved potency, selectivity and favorable pharmacokinetic properties. Importantly, this strategy allows access to new chemical space thus obtaining a better intellectual property position. A series of MCXs based on GSK-2126458, a known clinical PI3K/mTOR inhibitor is described. These molecules showed potent biochemical and cellular dual PI3K/mTOR inhibition, demonstrated strong antitumoral effects in human cancer cell lines, and displayed good drug-like properties. Among them, MCX 83 presented remarkable selectivity against a panel of 468 kinases, high in vitro metabolic stability, and favorable pharmacokinetic parameters without significant CYP450 and h-ERG binding inhibition. This profile qualified this compound as a suitable candidate for future in vivo PK-PD and efficacy studies in mouse cancer models.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Phosphatidylinositol 3-Kinases - pharmacology, therapeutic use
- Protein Kinase Inhibitors - pharmacology, therapeutic use
- Pyridazines - administration & dosage
- Quinolines - pharmacology, therapeutic use
- Sulfonamides - pharmacology, therapeutic use
- TOR Serine-Threonine Kinases - metabolism
- Find related publications in this database (Keywords)
- Dual PI3K/mTOR inhibitors
- Anticancer therapies
- Macrocycles
- Drug-like properties
- Selectivity
- In vivo PK studies