Development of 2-Aminoadenine-Based Proteolysis-Targeting Chimeras (PROTACs) as Novel Potent Degraders of Monopolar Spindle 1 and Aurora Kinases

Monopolar spindle 1 (Mps1, also known as TTK) and Aurora kinase (AURK) A and B are critical regulators of mitosis and have been linked to the progression of various cancers. Here, we report the design, synthesis, and biological evaluation of a series of PROTACs (proteolysis-targeting chimeras) targeting TTK and AURKs. We synthesized various degrader molecules based on four different 2-aminoadenine-based ligands, recruiting either cereblon or VHL as the E3-ligase. Our research showed that the nature of the linker and modification of the ligand significantly influence the target specificity and degradation efficacy. Notably, compound <b>19</b>, among the most potent degraders, demonstrated robust proteasome-mediated degradation of TTK with <i>D</i> _max of 66.5% and DC₅₀ value (6 h) of 17.7 nM as compared to its structurally akin inhibitor control, <b>23</b>. The cytotoxicity of most of the synthesized chimeras against acute myeloid leukemia cell line MV4-11 was lower than that of the corresponding parent inhibitors. However, we could also identify degraders such as <b>15</b> and <b>26</b> that induce potent AURKA degradation and display comparable antiproliferative activities to their parent compound <b>SF1</b>. Compound <b>15</b> degrades AURKA with low DC₅₀ value of 2.05 nM, which is 77-fold and 21-fold more selective toward AURKB and TTK and has an EC₅₀ value of 39 nM against cancer MV4-11 cells. Overall, the observations we made with the degrader molecules we developed can further aid in the design and development of optimized TTK or AURK degraders for cancer therapy.