Recent Patents on Anti-Cancer Drug Discovery - Volume 3, Issue 1, 2008

Breast cancer is the most common malignancy afflicting Western women today and is responsible for many deaths due to metastatic disease. Upregulation of the plasminogen-activation system (PAS) has been shown to correlate with poor prognosis in metastatic breast cancer and targeting this system represents an attractive strategy for the development of anti-metastasis prophylactic drugs. Two promising classes of PAS-targeting agents are inhibitors of the serine protease activity of urokinase plasminogen activator (uPA) and antagonists of the interaction of uPA with its cell surface receptor (uPAR). This review begins with a brief overview of the role of PAS in cancer metastasis before describing in detail a subset of the small molecules and peptides from the patent literature that target either uPA activity or uPA/uPAR interactions for use as anti-metastasis drugs.

Taxol is a powerful and complex anti-cancer compound that was first isolated from the bark of the Pacific yew Taxus brevifolia. Although it offered huge potential as an anti-cancer agent, it experienced a long development period, attributed to by its low availability from its traditional source. Research into alternate sources and methods of production for Taxol have been crucial in meeting with demand for the drug. Three main avenues of research have resulted. Firstly, chemical syntheses of this complex diterpene consist of multiple steps and are not economically feasible due to their low yield. Developments have therefore concentrated on enhancing production in vivo. Efforts have been made to understand the enzymatic steps involved in the synthesis within the yew and innovations to produce Taxol and Taxol-like substances in high yield from cell cultures of Taxus species. An alternative stream of research focuses on endophytes as the producer of Taxol. Endophytes can be isolated from the yew tree and produce Taxol in culture. Encouraging findings with endophytes resulted in much interest in the prospect of using endophytes as the producer of Taxol and Taxol-like substances. This review also discusses patents and the future prospects of each of the main streams of production.

This review focuses on the recent patents and use of small-molecule inhibitors (SMIs) of Bcl-2 family proteins as therapeutic agents against cancer. Bcl-2 members are crucial regulators of apoptotic cell death. Apoptosis is an evolutionarily conserved process of programmed cell death that plays an essential role in organism development and tissue homeostasis. Several mechanisms exist allowing cells to escape programmed cell death among them is the overexpression of the antiapoptotic proteins. Cancer cells are often found to overexpress many of these members such as Bcl-2, Bcl-XL, Mcl-1, Bcl-w and A1/Bfl1 and are usually resistant to a wide range of anti-cancer drugs and treatments. Many groups have been working to develop anti-cancer drugs that block the function of anti-apoptotic Bcl-2 members, thus favoring cell death. Methods include the downregulation of Bcl-2 expression or the use of peptides or small organic molecules to the Bcl-2 binding pocket, preventing its sequestration of proapoptotic proteins such as Bid and Bim. One of the most promising aspects of SMIs in treating cancer is that their targets and mechanisms of action are different from those of cytotoxic drugs and radiation. This makes it feasible to combine SMIs with other treatments, creating a synergistic therapy, without likely development of cross-resistance or increased toxicity. A broad-spectrum or “pan” SMI which targets multiple Bcl-2 family proteins is the goal.

As the most frequently mutated oncogene in human cancers, the small GTPase Ras is a logical target for anticancer drug development. Ras proteins serve as molecular switches regulating many key signaling processes, including growth-promoting pathways critical for normal cell functions that go awry in cancer. How to interfere selectively and successfully in oncogenic Ras function has proved to be surprisingly vexing. The complexity and importance of controlling correct subcellular localization supports the development of inhibitors that disrupt specific aspects of Ras membrane binding. Here, we concentrate on assays and compounds relevant to inhibiting enzymes responsible for post-translational modifications required for full processing and correct localization of Ras proteins or their targets. Common modifications include farnesylation (by farnesyltransferase, FTase) or geranylgeranylation (GGTase I), proteolysis (Rce1) and carboxymethylation (Icmt), as well as palmitoylation (PATs) and phosphorylation (PKC). We discuss history, current status and prospects of inhibitors designed to block these steps of prenyl and postprenyl processing of Ras itself, or that appear to compete with oncogenic Ras (farnesyl-S-thiosalicylic acid, FTS) for key membrane binding sites that dictate its ability to transduce specific oncogenic signals. Recent patents focusing on GGTIs, Icmt and PATs, and on novel approaches to Ras inhibition, are emphasized.

Tumor secreted proteins/peptides (tumor secretome) act as mediators of tumor-host communication in the tumor microenvironment. Therefore, development of anti-cancer drugs targeting secretome may effectively control tumor progression. Novel techniques including a capillary ultrafiltration (CUF) probe and a dermis-based cell-trapped system (DBCTS) linked to a tissue chamber were utilized to sample in vivo secretome from tumor masses and microenvironments. The CUF probe and tissue chamber were evaluated in the context of in vivo secretome sampling. Both techniques have been successfully integrated with mass spectrometry for secretome identification. A secretome containing multiple proteins and peptides can be analyzed by NanoLC-LTQ mass spectrometry, which is specially suited to identifying proteins in a complex mixture. In the future, the establishment of comprehensive proteomes of various host and tumor cells, as well as plasma will help in distinguishing the cellular sources of secretome. Many detection methods have been patented regarding probes and peptide used for identification of tumors.

Celecoxib (Celebrex, Pfizer, NY, USA) is a worldwide top branded COX-2-specific inhibitor. It was shown to provide relief of arthritic pain and inflammation and has recently been under investigation for the prevention and treatment of cancer. However, recent studies showed that long term use of high doses of celecoxib is associated with an increased cardiovascular toxicity. We discovered that the addition of curcumin, a natural COX-2 inhibitor, to celecoxib synergistically (up to 1000%) augments the growth inhibitory effects of celecoxib in in-vitro and in-vivo models of arthritis and cancer, thus rendering effective action of the drug at up to tenfold lower dose. This may pave the way for a novel strategy to treat arthritis and cancer because its effect [1] can be achieved in the serum of patients receiving standard anti-inflammatory or anti-neoplastic dosages of celecoxib, and [2] involves a regimen with a very low profile of side effects. Preliminary data suggest that the combination is not limited only to celecoxib and that addition of curcumin to other NSAIDs such as sulindac, synergistically augments neoplastic cell growth inhibition. Based on these finding we received an IRB approval to evaluate celecoxib+curcumin in patients with osteoarthritis, pancreatic cancer and metastatic CRC. We hope to complete these novel human clinical trials, in 12-18 months.

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