Novel high-affinity PARP inhibitors with various properties for imagining and treating cancer and inflammation-related diseases

The poly(ADP-ribose) polymersase-1 (PARP-1) enzyme is heavily involved in propagating neurodegeneration and cancer. In neurodegeneration PARP-1 causes cell death, while in cancer PARP-1 acts as DNA damage response enzyme that promotes survival of cancer cells with mutations within DNA repair genes. Therefore, PARP-1 inhibitors are used for treatment of cancers that harbor DNA repair genes mutations, such as BRCA-1 and BRCA-2. PARP-1 can also serves as a target for delivery of therapeutics radionuclides including alpha, beta, and auger emitting radionuclides. In neurodegeneration, PARP-1 can serve as a biomarker of neurodegeneration and as a therapeutic target for treating neuroinflammation.

Dr. Mach and his team at Penn investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. The team developed several first in class compounds that show high PARP-1 affinity and various catalytic inhibition, DNA damage properties, and cytotoxicity. These new drugs potentially can be used 
  -  as PET imaging agents for neurodegenerative diseases;
  -  as PET diagnostic agents for determining PARP-1 expression in patient’s tumor prior to treatment with PARP-1 inhibitors;
  -  to deliver cytotoxic radionuclides directly to cancer chromatin;
  -  for treatment of PARP-1-mediated neurodegeneration;
  -  for treatment of cancers harboring DNA repair genes mutations; and
  -  for treating inflammatory related diseases. 

• High PARP-1 affinity
• Various cytotoxicity
• Reduced drug efflux through pump P glycoprotein
• Potentially increased access to brain

• Cancer imagining, therapy, and radiotherapy
• Neuroimaging and neuroinflammation treatment