Cancer is a group of more than 200 diseases affecting different parts of the body. They share one common characteristic, unchecked cell growth progressing towards unlimited expansion, and yet require different approaches for its treatment. Both radiation therapy and chemotherapeutic drugs such as alkylating agent, anti-metabolites, topoisomerase inhibitors are designed to damage DNA to prevent cancer cells from growing. Poly (ADP-ribose) polymerases (PARPs) are a family of enzymes that catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) onto acceptor proteins. Among this family, which consists of at least 17 members, PARP-1 is the most widely investigated. It is postulated that the effect of chemotherapy and radiation therapy is dampened by DNA repair enzymes belonging to the PARP family.
PARP-1 is primarily (and to minor extent, PARP-2) involved in the initiation of repair processes during the onset of single strand breaks in DNA; this is achieved by recruiting repair proteins to the damaged DNA site. This PARP−DNA binding event activates the ADP ribosyl transferase (ART) catalytic domain which can auto-poly-ADPribosylate (PARylate) adjacent domains on PARP. This auto-PARylation event recruits DNA repair enzymes to the site of the damage but also triggers the release of PARP-1/-2 from DNA. It is one of the targets widely used in anticancer drug design and is involved in many cellular processes, serving as a “sensor” for DNA strand breaks.
Increased PARP-1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. PARP inhibitors are a new class of anticancer agents targeting DNA repair mechanisms. Most of the PARP inhibitors currently undergoing clinical trials in oncology are unselective PARP-1/-2 inhibitors. PARP-2, the closest isoform of PARP-1, has several reported physiological functions other than its subsidiary role in DNA repair. These considerations inspired our efforts toward developing selective PARP-1 inhibitors as potentially better tolerated drugs. The inhibition of PARP-1 is of clinical importance in diverse types of cancer. PARP-1 inhibitors have shown great potential to target cancers such as high-grade ovarian cancers and triple-negative breast cancers which are resistant to current treatment. PARP-1 inhibitors can be used both as a monotherapy to selectively kill cancer cells and in combination with chemotherapy.
Waverley Pharma has developed a strong PARP-1 inhibitor program. Discover the pipeline of novel compounds selective in inhibition of PARP-1 enzyme.
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Cancer is a major threat to the lives and health of people around the world, and the development of effective antitumor drugs that exhibit fewer toxic effects is an important aspect of cancer treatment. PARP inhibitors are antitumor drugs that target pathways involved in DNA-damage repair. The currently approved PARP inhibitors in the market include Olaparib, Niraparib, Rucaparib, Talazoparib, Fuzuloparib, Veliparib, Pamiparib, etc. While various PARP inhibitors have shown promise in cancer therapy, the FDA has recently voiced concerns about the currently approved PARP inhibitor class of drugs, due to unwanted side effects from their PARP-2 inhibition activity, alongside the desired PARP-1 inhibition. Hematological toxicities associated with the simultaneous inhibition of PARP-1 and PARP-2 have limited the clinical applications of these drugs. Therefore, the development of selective PARP-1 (vs PARP-2) inhibitors has become necessary to over come these challenges and develop effective antitumor drugs with fewer toxic effects. Selective PARP-1 inhibitors not only achieve antitumor effects, but also have the potential to reduce toxic effects associated with PARP-2 inhibition, underscoring the importance of the study and discovery of selective PARP-1 inhibitors. As a result, PARP-1 remains an attractive target for anti cancer drug development. The development of suitable small PARP-1 inhibitory molecules exhibiting PARP-1 selectivity and desired pharmacodynamic / pharmacokinetic properties is an inevitable direction for the development of PARP inhibitors.
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