Discovery of multiple kinases inhibitors, DBPR114, as the novel anti-cancer agent

[[abstract]]Purpose: The goal of targeted therapy is to identify the suitable target molecules to be inhibited, in order to achieve the best antitumor effect. The classical viewpoint is that inhibitor acting on single target allows selectivity and less adverse effect. However, clinical experience revealed that almost relapsed cancer patients developed drug resistance, often due to the activation or development of alternative signaling pathways or mutations that single target drugs are unable to effectively inhibit them. A current trend in the development of kinase inhibitors is the assumption that multi targeted therapy, which targets at several signaling pathways simultaneously, is more effective than single targeted therapy. Thus, paradigm in designing new anticancer drug is shifted: The drugs that act on multiple targets might have a better chance of inhibiting cancer cell proliferation than drugs that act on a single target. The objective of this research is aimed at identifying a multi-targeted kinase inhibitor as a development candidate for cancer therapy. Material and Method: We established Structure–Activity Relationship (S.A.R.) study based on 800 compounds that were synthesized by High Throughput Parallel Synthesis. Scaffold hopping approach by changing pharmacophore moiety had led us to discover DBPR114 as a multiple-targeted kinase inhibitor. Results: We discovered a novel multiple-targeted kinase inhibitor, DBPR114, that effectively inhibited 15 kinases in a panel of 57 oncogenic related kinases profiling, particularly against to Aurora kinase A and B, FLT-1, FLT-3 and c-Met in nanomolar range. In pharmacological study, DBPR114 significantly shrank tumor in 8 different xenograft models including Mia-Paca2, AsPC-1 (pancreatic carcinoma), Hep3B (hepatocellular carcinoma), MKN-45 (gastric carcinoma), MOLM-13 and MV4;11 (acute myeloid leukemia), NTUB-1 (bladder cancer), and Colo-205 (colorectal carcinoma) at a dose of 3 to 20 mg/kg by intravenous administration without significant adverse effect in most group of in vivo evaluations. Conclusion: This multiple targeting inhibitory properties plays a major role to shrinks tumor growth of various cancer cells in vivo and in vivo such as MOLM-13, MV4;11, MKN45, Colo-205, Mia-Paca2 and NTUB-1. The broad spectrum of anti-tumor activity of BPR1K0871 provides a great potential to become a promising multi-targeted kinase inhibitors as next generation of anti-cancer drug