PARPs

Poly(ADP-ribose)polyrmerase (PARP) inhibitors, 42 (2004) 125 P2 Purinoreceptor ligands, 38 (2001) 115 p38 MAP kinase inhibitors, 38 (2001) 1 Paclitaxel, anticancer agent, 32 (1995) 289... 

Ame J-C et al. PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem 1999 274 17860-17868. 

The knockout of PARP-1 or PARP-2 significantly reduces the cells ability to repair damaged DNA following their exposure to radiation or cytotoxic insult [6,7]. Poly (ADP-ribose) polymer synthesis consumes substantial amounts of NAD+, and hyperactivation of PARP results in depletion of cellular NAD+ pools and energy stores, leading to cell death by necrosis. 

Genomic sequence analysis has identified 17 structurally related proteins containing a PARP catalytic domain [3] however, closer inspection suggests that only PARPs 1-3, PARP-4 (vault PARP), and tankyrases 1 and 2 may truly function as poly(ADP-ribosyl)ating proteins. The remaining... 

SYNTHETIC LETHALITY OF INHIBITING PARP-1 AND PARP-2 IN BRCA MUTANT TUMORS... 

To evaluate PARP inhibition in a realistic setting, olaparib (7) was tested in a BrcflI / p53 / mouse breast cancer model. Treatment with olaparib caused tumor growth inhibition without generating signs of toxicity [14]. Interestingly, upon cessation of treatment and tumor... 

More recently, an alternative series of 2-alkoxybenzamides was designed where an intramolecular hydrogen bond mimics the phthalazinone scaffold [19]. Gratifyingly 8 exhibited good PARP inhibition, IC50 = 18 nM. 

The majority of PARPi bear close resemblance to nicotinamide (1), although notable exceptions include imidazoloquinolinones 33 and imi-dazolopyridine 34. Despite the absence of the classical amide group, these derivatives are dual PARPI/2 inhibitors with pIC50 8.36, and 6.40 for PARP-1, respectively. Both compounds are reversible NAD+-competitive inhibitors [34]. 

Another chemotype displaying appreciable isoform selectivity is the 5-benzoyloxy-3,4-dihydroisoquinolin-l(2H)-one (37), displaying ICso = 0.8 and 13 pM against PARP-2 and PARP-1, respectively [36]. Interestingly, 38 is a selective PARP-1 inhibitor, pICso = 7.35, displaying around 100-fold selectivity for PARP-1 over PARP-2 [34],... 

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