TY - JOUR
T1 - Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression
AU - Lakkaniga, Naga Rajiv
AU - Zhang, Lingtian
AU - Belachew, Binyam
AU - Gunaganti, Naresh
AU - Frett, Brendan
AU - Li, Hong yu
N1 - Funding Information:
This work was supported by the Arkansas Research Alliance research grant awarded to HYL. The molecular dynamics simulations were performed using a graphic card provided by NVIDIA.
Funding Information:
This work was supported by the Arkansas Research Alliance research grant awarded to HYL. The molecular dynamics simulations were performed using a graphic card provided by NVIDIA.
Publisher Copyright:
© 2020 Elsevier Masson SAS
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - Anti-Cancer drugs
KW - Aurora kinase B
KW - Kinase inhibitors
KW - Non-ATP competitive Inhibition
KW - Structure activity relationship (SAR)
KW - Synthetic lethal toxicity
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U2 - 10.1016/j.ejmech.2020.112589
DO - 10.1016/j.ejmech.2020.112589
M3 - Article
C2 - 32717530
AN - SCOPUS:85088212478
SN - 0223-5234
VL - 203
JO - European journal of medicinal chemistry
JF - European journal of medicinal chemistry
M1 - 112589
ER -