2. Academic Validation
  3. 2-Phenoxy-3, 4'-bipyridine derivatives inhibit AURKB-dependent mitotic processes by disrupting its localization

2-Phenoxy-3, 4'-bipyridine derivatives inhibit AURKB-dependent mitotic processes by disrupting its localization

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114904. doi: 10.1016/j.ejmech.2022.114904.
Gang Lv 1,  Qiong Shi 2,  Ting Zhang 3,  Jinhua Li 3,  Julia Kalashova 3,  Yan Long 3,  Yin Sun 4,  Chao Li 4,  Namrta Choudhry 3,  Hongmei Li 3,  Chenglu Yang 3,  Xiaohu Zhou 4,  Mallu Chenna Reddy 5,  Kishore Kumar Anantoju 5,  Rajesh Jupelli 5,  Shenqiu Zhang 2,  Jing Zhang 2,  Thaddeus Allen 6,  Hong Liu 6,  Naganna Nimishetti 7,  Dun Yang 8
Affiliations

Affiliations

  • 1 Chengdu Anticancer Bioscience, Chengdu, 610000, China; J. Michael Bishop Institute of Cancer Research, Chengdu, 610000, China. Electronic address: [email protected].
  • 2 J. Michael Bishop Institute of Cancer Research, Chengdu, 610000, China.
  • 3 Chengdu Anticancer Bioscience, Chengdu, 610000, China; J. Michael Bishop Institute of Cancer Research, Chengdu, 610000, China.
  • 4 Chengdu Anticancer Bioscience, Chengdu, 610000, China.
  • 5 Anticancer Bioscience (India), Hyderabad, 500051, India.
  • 6 Anticancer Bioscience (US), South San Francisco, CA, 94080, USA.
  • 7 Chengdu Anticancer Bioscience, Chengdu, 610000, China; J. Michael Bishop Institute of Cancer Research, Chengdu, 610000, China. Electronic address: [email protected].
  • 8 Chengdu Anticancer Bioscience, Chengdu, 610000, China; J. Michael Bishop Institute of Cancer Research, Chengdu, 610000, China. Electronic address: [email protected].
PMID: 36413818 DOI: 10.1016/j.ejmech.2022.114904
Abstract

Activity-based drug screens have successfully led to the development of various inhibitors of the catalytic activity of aurora kinases (AURKs), major regulatory kinases of cell division. Disrupting the localization of AURKB, rather than its catalytic activity, represents a largely unexplored alternative approach to disabling AURKB-dependent processes. Localization disruptors could be just as specific as direct inhibitors of AURKB activity, may bypass their off-target and select on-target toxicities, and are likely less susceptible to drug resistance resulting from mutations of the AURKB catalytic site. In this study, we demonstrate that the pan-AURK inhibitor AMG900 works at a low concentration not by inhibiting the phosphorylation of H3 at Ser10, an AURKB substrate, but by disrupting the mitotic localization of AURKB. Structural deletion studies pinpoint this undescribed activity to the 2-phenoxy-3,4'-bipyridine moiety of AMG900. Guided by a mechanism-informed phenotypic screening (MIPS) assay, the drug fragment is optimized into a novel class of inhibitors that, at low nanomolar concentrations, can disable AURKB through disruption of its mitotic localization and have desirable oral PK properties. Hierarchical clustering of cell fitness profiles reveals that these compounds cluster with each other, rather than with known AURK inhibitors such as AMG900 and VX-680. Validation studies in mice demonstrate that compound 15a elicits mitotic arrest and Apoptosis in NCI-H23 human lung adenocarcinoma xenografts, resulting in a pronounced suppression of tumor growth. The discovery and optimization of compounds that disrupt AURKB localization are successfully facilitated by MIPS. Our findings suggest that 2-phenoxy-3, 4'-bipyridine derivatives have the potential to be further developed as effective therapeutics for the treatment of malignancy by delocalizing AURKB.

Keywords

2-Phenoxy-3; 4′-bipyridine; AMG900; AURKB; Malignancy; Mechanism-informed phenotypic screening.

Figures
Products