Abstract
Multiple myeloma is a rare blood cancer that develops from abnormal plasma cells in the bone marrow. Treatment of multiple myeloma remains an enormous challenge. In this work, hybrid compounds are developed and studied for their potential use against multiple myeloma. The compounds are designed to act by a dual mechanism of action, activation of the p53 pathway, and inhibition of the ataxia telangiectasia and Rad3-related protein (ATR). To evaluate the selectivity for the p53 pathway, the compounds are first evaluated in an isogenic pair of HCT116 colon cancer cell lines, with and without p53, and in two breast cancer cell lines expressing different forms of p53. Then, the growth inhibitory effect of the hybrid compounds is tested against the multiple myeloma cell lines RPMI 8226 (mutant p53) and MM.1S (wild-type p53). At the same time, compound 15 is confirmed to inhibit doxorubicin- but not UV-induced DNA damage response via the ATR/Chk1 signaling pathway. The hybrids show lower IC(50) values compared to the fragments alone, highlighting the potential for using hybrid molecules containing two pharmacophores with complementary activities. These results suggest that novel hybrid molecules may serve as new leads against multiple myeloma.