Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins

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 13 was identified,
which potently (IC50 < 200 nM) inhibited the proliferation
of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic
optimization of 13 by prodrug strategies resulted in
orally bioavailable 25, which demonstrated an 8-fold
higher oral AUC (F = 62.3%). Pharmacodynamic studies
of 25 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 25 for
the treatment of MYC-amplified cancers including
SCLC.