Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins
| Autor: | Mine-Hsine Wu, Chuan Shih, Yen-Ting Chen, Teng-Kuang Yeh, Ya-Hui Chi, Yan-Fu Chen, Jen-Shin Song, Ming-Chun Hung, Wan-Ping Wang, Jing-Ya Wang, Ching-Ping Chen, Jen-Yu Yeh, Yu-Chieh Su, Pei-Chen Wang, Yi-Yu Ke, Chia-Hua Tsai, Chiung-Tong Chen, Zhong-Wei Wu, Chun-Ping Chang, Wen-Hsing Lin |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Lung Neoplasms Pyrimidine Drug Evaluation Preclinical Aurora A kinase Aurora inhibitor Down-Regulation 01 natural sciences Article Proto-Oncogene Proteins c-myc Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Aurora kinase Downregulation and upregulation Drug Discovery Animals Aurora Kinase B Humans Protein Kinase Inhibitors neoplasms IC50 Tumor xenograft Aurora Kinase A Cell Proliferation 030304 developmental biology Mice Inbred ICR 0303 health sciences Binding Sites Small Cell Lung Carcinoma Xenograft Model Antitumor Assays Small molecule 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Pyrimidines chemistry Drug Design Cancer research Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|