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

  • J Med Chem. 2021 Jun 10;64(11):7312-7330. doi: 10.1021/acs.jmedchem.0c01806.
Ya-Hui Chi  1  2 ,  Teng-Kuang Yeh  1 ,  Yi-Yu Ke  1 ,  Wen-Hsing Lin  1 ,  Chia-Hua Tsai  1 ,  Wan-Ping Wang  1 ,  Yen-Ting Chen  1 ,  Yu-Chieh Su  1 ,  Pei-Chen Wang  1 ,  Yan-Fu Chen  1 ,  Zhong-Wei Wu  1 ,  Jen-Yu Yeh  1 ,  Ming-Chun Hung  1 ,  Mine-Hsine Wu  1 ,  Jing-Ya Wang  1 ,  Ching-Ping Chen  1 ,  Jen-Shin Song  1 ,  Chuan Shih  1 ,  Chiung-Tong Chen  1 ,  Chun-Ping Chang  1  3
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 35053, Taiwan.
  • 2. Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.
  • 3. Department of Chemistry, Chung Yuan Christian University, Taoyuan 320314, Taiwan.
PMID: 34009981 DOI: 10.1021/acs.jmedchem.0c01806
Abstract

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.