Dong-Yao Wang; Yan Cao; Le-Yi Zheng; Lang-Dong Chen; Xiao-Fei Chen; Zhan-Ying Hong; Zhen‐Yu Zhu; Xiaoyu Li; Yi-Feng Chai
Chem. Eur. J., 2017, 23, 10906-10914
https://doi.org/10.1002/chem.201702033

Abstract

Accurate identification of the molecular targets of bioactive small molecules is a highly important yet challenging task in biomedical research. Previously we have developed a method named DPAL (DNA-Programmed Affinity Labelling) for labelling and identifying the cellular targets of small molecules and nucleic acids. Here we applied DPAL for the target identification of Alisertib (MLN8237), a highly specific Aurora kinase A (AKA) inhibitor and a drug candidate being tested in clinical trials for cancer treatment. Besides its well-established target of AKA, several potential new targets of MLN8237 were identified. Among them, p38 mitogen-activated protein kinase (p38) and laminin receptor (LAMR) were validated to be implicated in the anti-cancer activities of MLN8237. Interestingly, these new targets were not identified with non-DNA-based affinity probes either in our experiments or in previous studies. This work may facilitate the understanding the molecular basis of the efficacy and side-effects of MLN8237 as a clinical drug candidate. On the other hand, this work has also demonstrated that the method of DPAL could be a useful tool for target identification of bioactive small molecules.