Discovery of novel 7,8-dihydro-1H-purine derivatives as potent dual DNA-PK/HDAC inhibitors against solid tumors.

DNA-PK, a key kinase in the Non-Homologous End Joining (NHEJ) DNA repair pathway, shows limited antitumor effects when used alone. Our previous work demonstrated that HDAC inhibitors enhance the cellular DNA damage response. We therefore designed novel DNA-PK/HDAC dual inhibitors for anticancer assessment. Amongst, DH-6 was identified as the most potent candidate with well-balanced inhibitory activities against DNA-PK and HDAC6 (IC50 = 34.22, 241.2 nM) and exhibited relatively moderate antiproliferative potency. Moreover, the accumulation of Ac-α-tubulin and regulation of the expression levels of γ-H2AX and p-DNA-PK induced by DH-6 were verified. Notably, DH-6 displayed good antitumor efficacy in multiple solid-tumor models, overcoming the limited antitumor activity associated with DNA-PK inhibitor monotherapy. Furthermore, DH-6 also enhanced the therapeutic efficacy of the chemotherapeutic drug doxorubicin in mouse models bearing colorectal and breast tumors, identifying DH-6 as a lead for further development of DNA-PK/HDAC dual inhibitors and demonstrating its effective sensitizing effects to chemotherapy in colorectal and breast cancers.