Acute myeloid leukemia (AML), an aggressive and frequently fatal hematologic malignancy, is one of the most common type of leukemia in children and adolescents. In this work, we report the design and synthesis of a quinazoline-based multi-kinase inhibitor for the treatment of AML and other malignancies. Based on the previously reported furanopyrimidine 3, quinazoline core containing lead 4 was synthesized with dual FLT3/AURKA inhibition (IC50 = 127/5 nM) as well as improved physicochemical properties. Detailed structure-activity relationship study in the lead 4 allowed FLT3 and AURKA inhibition to be finely tuned, resulting in AURKA selective, FLT3 selective and dual FLT3/AURKA selective (BPR1K871; IC50 = 19/27 nM) agents. BPR1K871 showed potent anti-proliferative activities in MOLM-13 and MV4-11 AML cells (EC50 ~ 5 nM). Moreover, kinase profiling and cell-line profiling revealed BPR1K871 to be a potential multi-kinase inhibitor. In vivo efficacy in AML xenograft models (MOLM-13 and MV4-11), as well as in solid tumor models (COLO205 and Mia-PaCa2), led to the selection of BPR1K871 as a preclinical development candidate for anti-cancer therapy. Further detailed studies could help to investigate the full potential of BPR1K871 as a multi-kinase inhibitor.

Discovery of BPR1K871 – a quinazoline based multi-kinase inhibitor for the treatment of AML and solid tumors: Rational design, synthesis, in vitro and in vivo evaluation

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.