2. Academic Validation
  3. Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins

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

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.

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