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

Naga Rajiv Lakkaniga, Lingtian Zhang, Binyam Belachew, Naresh Gunaganti, Brendan Frett, Hong yu Li

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Article number112589
JournalEuropean Journal of Medicinal Chemistry
Volume203
DOIs
StatePublished - Oct 1 2020
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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