Discovery of N-(3-fluorophenyl)-2-(4-((7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-yl)amino)phenyl)acetamide as the first orally active selective aurora kinase B inhibitor.

Cell cycle deregulation is a crucial hallmark of tumorigenesis, leading to uncontrolled cell growth. Overexpression of serine/threonine aurora kinase B (AURKB) is a common feature of human cancer, particularly of the most aggressive subtypes, and it contributes to the alteration of the cell cycle. Thus, AURKB is considered a promising target for cancer treatment; however, no AURKB pharmacological inhibitor has been approved so far. We previously reported SP-96, a quinazoline non-ATP competitive AURKB inhibitor, which exhibited sub nanomolar activity in enzymatic assay. However, SP-96 cellular activity was hampered by its poor cellular activities. Herein, we designed and synthesized a new series of quinazoline derivatives featuring improved membrane penetration. Compound 4b demonstrated efficacy in human cancer-derived cells and was orally active at low dose in a mouse xenograft model and correlated with the drug concentration in plasma. Importantly, a closely related compound 7o attached with solubilizing group is orally bioavailable in rats. In conclusion, compounds 4b and 7o represents a promising lead series for further optimization to develop an oral clinical AURKB inhibitor candidate.