Τίτλος:
Design and synthesis of novel 7-aminosubstituted pyrido[2,3-b]pyrazines exhibiting anti-breast cancer activity
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Breast cancer (BrCa) remains an unmet medical need despite the revolutionary development of antibody treatments and protein kinase inhibitors. In the current study, a series of novel substituted pyridopyrazine derivatives have been rationally designed and evaluated as multi-kinase inhibitors in the PI3K pathway. The target compounds were prepared from 6-amino-2-picoline, which upon nitration and selective reduction was converted to suitably substituted 6-methyl-7-aminopyrido[2,3-b]pyrazines. Suitable manipulation of the former amines provided the designed analogues, which were then assessed in vitro against several BrCa cell lines using the MTT cytotoxicity assay. The most potent compounds underwent evaluation in a broad spectrum of protein kinases, while their pharmacokinetic parameters were measured by LC-MS/MS. In vivo evaluation of a hit compound (14a) was performed in a HER2 amplified BrCa xenograft model (HCC1954) and efficacy was determined using Western blot based phosphokinase assays and immunohistochemistry. This derivative showed low micromolar cytotoxic potency in all BrCa cell lines, a mild inhibition of the PI3Kα wild type and H1047R mutated enzyme and excellent pharmacokinetic parameters following oral and intraperitoneal administration at the designed dose of 10 mg/kg, with absence of in vivo phenotypic toxicity. Interestingly, compound 14a inhibited the growth of xenografted tumors. Analysis of excised tumors from the treated animals showed a significantly reduced population of Ki-67 positive cells, as well as downregulated levels of phosphorylated AKT, ERK1/2 and SRC compared to vehicle treated animals. Finally, the specificity of 14a was assessed in a panel of 31 kinases where a mild, but direct, inhibition of the MET receptor tyrosine kinase was observed. © 2016 Elsevier Masson SAS
Συγγραφείς:
Argyros, O.
Lougiakis, N.
Kouvari, E.
Papafotika, A.
Raptopoulou, C.P.
Psycharis, V.
Christoforidis, S.
Pouli, N.
Marakos, P.
Tamvakopoulos, C.
Περιοδικό:
European Journal of Medicinal Chemistry
Εκδότης:
Elsevier Masson s.r.l.
Λέξεις-κλειδιά:
amine; antineoplastic agent; epidermal growth factor receptor 2; Ki 67 antigen; mitogen activated protein kinase 1; mitogen activated protein kinase 3; n (6 methyl 3 (phenylthio)pyrido [2,3 b]pyrazin 7 yl) n' phenylurea; phosphotransferase; pictilisib; protein kinase B; pyrazine derivative; scatter factor receptor; unclassified drug; antineoplastic agent; phosphatidylinositol 3 kinase; pyrazine derivative, animal experiment; animal model; antineoplastic activity; antiproliferative activity; Article; cancer inhibition; controlled study; cytotoxicity assay; drug design; drug efficacy; drug synthesis; enzyme phosphorylation; female; human; human cell; immunohistochemistry; in vitro study; in vivo study; liquid chromatography-mass spectrometry; mouse; nonhuman; pharmacokinetic parameters; structure activity relation; Western blotting; animal; antagonists and inhibitors; breast tumor; cell proliferation; chemistry; drug effects; drug screening; pathology; synthesis; tumor cell line, Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; Female; Humans; Mice; Phosphatidylinositol 3-Kinases; Pyrazines; Structure-Activity Relationship; Xenograft Model Antitumor Assays
DOI:
10.1016/j.ejmech.2016.12.025
