Discovery of the cancer cell selective dual acting anti-cancer agent ( Z )-2-(1 H -indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131)

摘要

Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound4awas first identified in a phenotypic screen in which HeLa cells treated with4amanifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that4acauses an increase in mitotic marker pH3 and autophagy marker LC3. Importantly4ainduces cell death in cancer cells while sparing normal cells which regrow after4ais removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed4aas the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI501.5?μM). In a mouse model of paclitaxel-resistant colon cancer,4ashowed 74% tumor growth inhibition when administered at a dose of 20?mg/kg IP twice a day.