Synthesis and evaluation of apoptosis induction of thienopyrimidine compounds on KRAS and BRAF mutated colorectal cancer cell lines

Stéphane Pédeboscq, Denis Gravier, Françoise Casadebaig, Geneviève Hou, Arnaud Gissot, Christophe Rey, François Ichas, Francesca De Giorgi, Lydia Lartigue, Jean-Paul Pometan
Bioorganic & Medicinal Chemistry. 2012-11-01; 20(22): 6724-6731
DOI: 10.1016/j.bmc.2012.09.034

Read on PubMed

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.

Know more about