Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins.
Chi YH, Yeh TK, Ke YY, Lin WH, Tsai CH, Wang WP, Chen YT, Su YC, Wang PC, Chen YF, Wu ZW, Yeh JY, Hung MC, Wu MH, Wang JY, Chen CP, Song JS, Shih C, Chen CT, Chang CP.
The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound <b>13</b> was identified, which potently (IC<sub>50</sub> < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of <b>13</b> by prodrug strategies resulted in orally bioavailable <b>25</b>, which demonstrated an 8-fold higher oral AUC (<i>F</i> = 62.3%). Pharmacodynamic studies of <b>25</b> showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of <b>25</b> for the treatment of <i>MYC</i>-amplified cancers including SCLC.