Synthesis and evaluation of apoptosis induction of thienopyrimidine compounds on KRAS and BRAF mutated colorectal cancer cell lines.
Monoclonal antibodies (MoAb) and tyrosine kinase inhibitors (TKI) targeting the EGFR (Epidermal Growth Factor Receptor) pathways are currently used in colorectal cancer treatment. Despite the improvement of median overall survival, resistance is observed notably due to KRAS and BRAF gene mutations. We synthesized four series of thienopyrimidines whose scaffold is structurally close to TKI used in clinical practice. We evaluated apoptosis induced by these compounds using flow cytometry on KRAS and BRAF mutated cell lines. Our results confirm that the mutated cell lines (HCT116 and HT29) are more resistant to apoptosis than the non-mutated cell line (Hela). Interestingly, among the 13 compounds tested, three of them (5b, 6b and 6d) and gefitinib exhibited a noteworthy pro-apoptotic effect, especially on mutated cell lines with an IC(50) value between 70 and 110μM. These three compounds seem particularly attractive for the development of novel treatments for colorectal cancer patients harboring EGFR pathway mutations.
Service Pharmacie, Hôpital Saint-André, CHU de Bordeaux, 1 rue Jean Burguet, Bordeaux, France. stephane.pedeboscq@chu-bordeaux.fr
Stéphane
S
Pédeboscq
Denis
D
Gravier
Françoise
F
Casadebaig
Geneviève
G
Hou
Arnaud
A
Gissot
Christophe
C
Rey
François
F
Ichas
Francesca
F
De Giorgi
Lydia
L
Lartigue
Jean-Paul
JP
Pometan
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D011743:Pyrimidines; C476003:thienopyrimidine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020169:Caspases; D018631:ras Proteins