Background/Objective: KRAS-mutant colorectal cancers (CRC) are tumors that are associated with
poor prognosis. However, no effective treatments are available to target them. Therefore, we designed and synthesized
novel chalcone analogs, small organic molecules, to investigate their effects on KRAS-mutant CRC cells.
Methods: Fourteen new chalcone analogs were synthesized, optimized, characterized, and tested against two
KRAS-mutant CRC cell lines (HCT-116 and LoVo), one p-53 and BRAF mutant CRC cell line (HT-29) and one
normal immortalized colon cells (NCE-1 E6/E7). Effects on cell viability, apoptosis, cell cycle, migration, colony
formation, EMT, and angiogenesis were investigated.
Results: Compounds 3 and 14 were the most effective. Compound 3 showed potent activity against HCT-116 and
LoVo cell lines (GI50 of 6.10 μM and 7.00 μM, respectively). While compound 14 showed GI50 of 8.60 μM and
8.80 μM on HCT-116 and LoVo cell lines, respectively. Both compounds were approximately 2-3 times more
selective toward cancer cells rather than normal colon cells. Compound 3 was effective in inducing apoptosis in
HCT-116 cells via Bax upregulation and Bcl-2 downregulation. Invasion and metastasis of KRAS-mutant cells
were modulated by compounds 3 and 14 through significant inhibition of cell migration and the prevention of
colony formation. In addition, they reversed EMT by downregulation of EMT markers (vimentin, fascin, and β-
catenin) and upregulation of cell-cell adhesion marker, E-cadherin. Furthermore, compounds 3 and 14 had significantly
inhibited angiogenesis in ovo.
Conclusion: Compounds 3 and 14 represent potent and selective leads for KRAS-mutant CRC cells, thus, further
in vitro and in vivo studies are necessary to confirm their effect on KRAS-mutant CRCs.