2. Academic Validation
  3. Discovery and optimization of novel phenyldiazepine and pyridodiazepine based Aurora kinase inhibitors

Discovery and optimization of novel phenyldiazepine and pyridodiazepine based Aurora kinase inhibitors

  • Bioorg Chem. 2020 Jun;99:103800. doi: 10.1016/j.bioorg.2020.103800.
Natarajan Tamizharasan 1,  Chandru Gajendran 2,  Rajendra Kristam 3,  Suresh P Sulochana 4,  Dhanalakshmi Sivanandhan 2,  Ramesh Mullangi 4,  Logesh Mathivathanan 5,  Gurulingappa Hallur 6,  Palaniswamy Suresh 7
Affiliations

Affiliations

  • 1 Supramolecular and Catalysis Lab, Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India; Medicinal Chemistry Department, Jubilant Biosys Ltd., Bangalore 560022, Karnataka, India.
  • 2 Oncology Department, Jubilant Biosys Ltd., Bangalore 560022, Karnataka, India.
  • 3 Computational Chemistry Department, Jubilant Biosys Ltd., Bangalore 560022, Karnataka, India.
  • 4 Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd., Bangalore 560022, Karnataka, India.
  • 5 Florida International University, 11200, SW 8(th) St, Miami, FL 33199, USA.
  • 6 Medicinal Chemistry Department, Jubilant Biosys Ltd., Bangalore 560022, Karnataka, India. Electronic address: [email protected].
  • 7 Supramolecular and Catalysis Lab, Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India. Electronic address: [email protected].
PMID: 32283344 DOI: 10.1016/j.bioorg.2020.103800
Abstract

Aurora B plays critical role in the process of chromosome condensation and chromosome orientation during the regulation of mitosis. The overexpression of Aurora B has been observed in several tumor types. As a part of our ongoing effort to develop Aurora B inhibitors, herein, we described the design, synthesis and evaluation of phenyl/pyridine diazepine analogs. The diazepane aniline pyrimidine (4a) was identified as an initial hit (Aurora B IC50 6.9 µM). Molecular modeling guided SAR optimization lead to the identification of 8-fluorobenzodiazepine (6c) with single digit nM potency (Aurora B IC50 8 nM). In the antiproliferation assay 6c showed activity across the cell lines with IC50 of 0.57, 0.42, and 0.69 µM for MCF-7, MDA-MB 231, and SkoV3 respectively. In the in vivo PK profile. 6c has shown higher bioavailability (73%) along with good exposure (AUC of 1360 ng.h/mL).

Keywords

Aurora kinase inhibitor; Oncology; Phenyldiazepine; Pyridodiazepine.

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