Poly (ADP ribose) Polymerase Inhibitors
Inotek’s PARP inhibitors are potent inhibitors of the nuclear enzyme poly(ADP ribose) polymerase (PARP), a scientifically validated and clinically relevant target for diseases mediated by cell necrosis, DNA repair abnormality, and inflammation. Under normal conditions, PARP is involved in the repair of DNA single strand breaks caused by oxidative stress via the activation and recruitment of DNA repair enzymes in the nucleus. Under conditions where DNA damage is excessive (such as by acute excessive exposure to a pathological insult), PARP is over-activated, resulting in cell-based energetic failure characterized by NAD depletion and leading to ATP consumption, cellular necrosis, tissue injury, and organ damage/failure. Consequently, PARP inhibitors have several potential clinical benefits:
Prevention of ischemia, reperfusion injury and inflammation prior to clinical interventions known to induce cell necrosis: Pharmacologic blockade of the PARP cell death pathway prevents oxidant-mediated cell death and organ dysfunction. In extensive pre-clinical in vivo studies, Inotek’s PARP inhibitors have consistently demonstrated the ability to block the enzymatic activity of PARP-1 and PARP-2 and thereby protect tissues from ischemia, reperfusion injury, and inflammatory damage.
Treatment of tumors refractory to chemotherapy alkylating agents: PARP-1 is required for base excision repair (BER) of DNA bases alkylated by chemotherapeutic agents such as temozolomide (TMZ). Eight independent research groups, including Inotek, have unequivocally demonstrated a benefit of PARP inhibition in augmenting the effects of alkylating agents (TMZ) and other cancer therapies (e.g. topoisomerase inhibitors, anthracyclines, cis-platinum). PARP has also been shown to mediate resistance of malignant tissue to TMZ.
Treatment of tumors deficient in BRCA1 or BRCA2: In cases where tumors are deficient in BRCA1 or BRCA2 (proteins which play a role in DNA double strand break repair), such as certain types of breast and ovarian cancer, a PARP inhibitor may be used alone to arrest the growth and potentially kill dividing tumor populations.
Inotek’s PARP Inhibitors are in preclinical development for oncology and other indications. The company has PARP inhibitors which exhibit profiles suitable for both oral and intravenous administration in a variety of clinical indications.