Research & Development

PARP-1 Inhibitors

New Drug Discovery Program

Cancer is a group of more than 200 diseases affecting different parts of the body. They all share one common characteristic, unchecked cell growth progressing towards unlimited expansion and 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 in order to prevent cancer cells from growing.

It is postulated that the effect of chemotherapy and radiation therapy is dampened by DNA repair enzymes 1 Poly (ADP-Ribose) Polymerase-1 (PARP-1) belongs to the PARP family of enzymes and is involved in the detection  and repair of DNA damage. PARP-1 inhibitors are a new class of anticancer agents agents targeting DNA repair mechanism. The inhibition of PARP-1 is of clinical importance in various 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 inhibitor can be used both as a monotherapy to selectively kill cancer cells and also in combination.

Within the last decade, PARP inhibitorshave emerged as a promising class of anticancer agents, showing efficacy invarious types of cancer. While various PARP inhibitors have shown promise incancer therapy, the FDA has recently voiced some concern about the currentlyapproved PARP inhibitor class of drugs as they have shown some unwanted sideeffects coming from their PARP-2 inhibition activity, alongside the desiredPARP-1 inhibition. Therefore, the development of selective PARP-1 (vs PARP-2)inhibitors has become necessary to overcome these challenges and developeffective antitumor drugs with fewer toxic effects.

Over the past few years, Waverley Pharmahas developed a strong PARP-1 inhibitor program, considering the recentconcerns highlighted by the FDA. Since PARP-1 selective inhibition is critical,Waverley Pharma’s PARP-1 program focuses on discovering both active andselective compounds towards PARP-1 inhibition. We have successfully identifiedseveral highly potent and highly selective PARP-1 lead compounds.

Many of Waverley Pharma’s compounds have singledigit nanomolar IC50 against PARP-1, like Olaparib and Saruparib(AZD5305) using in vitro PARP-1 assay kits. They also exhibit apromising PARP-1 versus PARP-2 selectivity, ranging from 50- to 800-fold. Our mostpromising lead compound, CAWP-1322, features a sub-nanomolar PARP-1 inhibitionactivity (IC50 < 0.2 nM), that is significantly more active thanSaruparib, and ~800-fold selectivity against PARP-2. Preliminary results showgood microsomal stability (in mouse and human liver) and an excellentselectivity against hERG channel inhibition (IC50 > 10 mM). More in vivo efficacy assays, bio-profiling assays, andPK studies are planned or already underway for selected compounds. WaverleyPharma also actively works to protect the intellectual property spacesurrounding the compounds of interest from its portfolio.

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