1. Academic Validation
  2. Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression

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

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: HLi2@uams.edu.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-131339
    99.42%, Aurora B 抑制剂