Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression

  • Eur J Med Chem. 2020 Oct 1;203:112589. doi: 10.1016/j.ejmech.2020.112589.
Naga Rajiv Lakkaniga  1 ,  Lingtian Zhang  1 ,  Binyam Belachew  2 ,  Naresh Gunaganti  1 ,  Brendan Frett  1 ,  Hong-Yu Li  3
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
  • 2. Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
  • 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. Electronic address: [email protected].
PMID: 32717530 DOI: 10.1016/j.ejmech.2020.112589
Abstract

Aurora Kinase B is a serine-threonine kinase known to be overexpressed in several cancers, with no inhibitors approved for clinical use. Herein, we present the discovery and optimization of a series of novel quinazoline-based Aurora Kinase B inhibitors. The lead inhibitor SP-96 shows sub-nanomolar potency in Aurora B enzymatic assays (IC50 = 0.316 ± 0.031 nM). We identified the important pharmacophore features resulting in selectivity against Receptor Tyrosine Kinases. Particularly, SP-96 shows >2000 fold selectivity against FLT3 and KIT which is important for normal hematopoiesis. This could diminish the adverse effect of neutropenia reported in the clinical trials of the Aurora B Inhibitor Barasertib, which inhibits FLT3 and KIT in addition to Aurora B. Enzyme kinetics of SP-96 shows non-ATP-competitive inhibition which makes it a first-in-class inhibitor. Further, SP-96 shows selective growth inhibition in NCI60 screening, including inhibition of MDA-MD-468, a Triple Negative Breast Cancer cell line.

Keywords
Anti-Cancer drugs; Aurora kinase B; Kinase inhibitors; Non-ATP competitive Inhibition; Structure activity relationship (SAR); Synthetic lethal toxicity.
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