Mechanism of BIP-4 mediated inhibition of InsP3Kinase-A

Biosci Rep. 2021 Jul 30;41(7):BSR20211259. doi: 10.1042/BSR20211259.

Abstract

Overexpression of the neuronal InsP3kinase-A increases malignancy of different tumor types. Since InsP3kinase-A highly selectively binds Ins(1,4,5)P3, small molecules competing with Ins(1,4,5)P3 provide a promising approach for the therapeutic targeting of InsP3kinase-A. Based on this consideration, we analyzed the binding mechanism of BIP-4 (2-[3,5-dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl]-5, 8-dinitro-1H-benzo[de]isoquinoline-1,3(2H)-dione), a known competitive small-molecule inhibitor of Ins(1,4,5)P3. We tested a total of 80 BIP-4 related compounds in biochemical assays. The results of these experiments revealed that neither the nitrophenyl nor the benzisochinoline group inhibited InsP3kinase-A activity. Moreover, none of the BIP-4 related compounds competed for Ins(1,4,5)P3, demonstrating the high selectivity of BIP-4. To analyze the inhibition mechanism of BIP-4, mutagenesis experiments were performed. The results of these experiments suggest that the nitro groups attached to the benzisochinoline ring compete for binding of Ins(1,4,5)P3 while the nitrophenyl group is associated with amino acids of the ATP-binding pocket. Our results now offer the possibility to optimize BIP-4 to design specific InsP3Kinase-A inhibitors suitable for therapeutic targeting of the enzyme.

Keywords: InsP3Kinase-A; nitro groups; selective inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Binding, Competitive
  • Catalytic Domain
  • Computer-Aided Design
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Kinetics
  • Molecular Docking Simulation
  • Molecular Structure
  • Mutation
  • Naphthalimides / chemistry
  • Naphthalimides / pharmacology*
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Binding
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-(3,5-dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl)-5,8-dinitro-1H-benzo(de)isoquinoline-1,3(2H)-dione
  • Enzyme Inhibitors
  • Naphthalimides
  • Pyrazoles
  • Adenosine Triphosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • Inositol 1,4,5-trisphosphate 3-kinase