Development of\n2‑Aminoadenine-Based Proteolysis-Targeting\nChimeras (PROTACs) as Novel Potent Degraders of Monopolar Spindle\n1 and Aurora Kinases

Monopolar spindle\n1 (Mps1, also known as TTK) and Aurora\nkinase\n(AURK) A and B are critical regulators of mitosis and have been linked\nto the progression of various cancers. Here, we report the design,\nsynthesis, and biological evaluation of a series of PROTACs (proteolysis-targeting\nchimeras) targeting TTK and AURKs. We synthesized various degrader\nmolecules based on four different 2-aminoadenine-based ligands, recruiting\neither cereblon or VHL as the E3-ligase. Our research showed that\nthe nature of the linker and modification of the ligand significantly\ninfluence the target specificity and degradation efficacy. Notably,\ncompound <b>19</b>, among the most potent degraders, demonstrated\nrobust proteasome-mediated degradation of TTK with <i>D</i><sub>max</sub> of 66.5% and DC<sub>50</sub> value (6 h) of 17.7 nM\nas compared to its structurally akin inhibitor control, <b>23</b>. The cytotoxicity of most of the synthesized chimeras against acute\nmyeloid leukemia cell line MV4-11 was lower than that of the corresponding\nparent inhibitors. However, we could also identify degraders such\nas <b>15</b> and <b>26</b> that induce potent AURKA degradation\nand display comparable antiproliferative activities to their parent\ncompound <b>SF1</b>. Compound <b>15</b> degrades AURKA\nwith low DC<sub>50</sub> value of 2.05 nM, which is 77-fold and 21-fold\nmore selective toward AURKB and TTK and has an EC<sub>50</sub> value\nof 39 nM against cancer MV4-11 cells. Overall, the observations we\nmade with the degrader molecules we developed can further aid in the\ndesign and development of optimized TTK or AURK degraders for cancer\ntherapy.