Recent Patents on Anti-Cancer Drug Discovery - Volume 9, Issue 3, 2014

It is now well established that hormonal pathways are involved in the development of prostate cancer towards the castration resistant (CRPC) stage and can be effective molecular targets for novel treatment strategies. Most CRPC are sensitive to androgens and this can be due to the intratumoral production of androgens, androgen receptor (AR) amplification/ mutations and epigenetic modifications of AR expression/signaling. Based on these observations, potent agents targeting the AR axis were developed: 1) inhibitors of CYP17 (a key enzyme in the production of androgens), such as abiraterone and orteronel; 2) AR antagonists that bind to AR and impair AR activation, such as enzalutamide and ARN-509. Moreover, gonadotropin-releasing hormone receptors (GnRH-R), associated with a strong antitumor activity, are expressed in CRPC cells, indicating that they might represent an important target for GnRH analog-based therapeutic strategies. In addition to GnRH agonists and antagonists (i.e., degarelix), cytotoxic GnRH-based bioconjugates, delivering chemotherapeutic drugs to cancer cells expressing the GnRH-R, were developed and reported to exert antitumor effects on CRPC cells; some of them (i.e., AN-152) have already entered clinical trials. This review discusses the most relevant patents and recent observations on the anti-cancer efficacy of novel drugs targeting the AR and the GnRH-R pathways in CRPC.

The genetic alterations and aberrant miRNA expression profiles have been identified as important events behind the emergence of cancer. This knowledge triggers the use of miRNA therapeutics as an anticancer strategy. Basically, MicroRNAs (miRNAs) are approximately 22-nucleotide long, endogenous non-protein-coding RNA molecules which function as important regulatory molecules that regulate gene and protein expression through the RNA interference (RNAi) machinery. Transcription of these molecules by RNA polymerases II and III, resulting in the generation of precursor microRNAs that undergo a series of cleavage events, consequently, generate the mature microRNA. The biogenesis pathway is mediated by the two important cleavage events such as nuclear and cytoplasmic. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC), leading to translational repression and hence, regulate the gene expression. The current progress in the development of strategies for miRNA-based anticancer therapies is due to its involvement in cellular, developmental and biological processes including regulation in cancer cell and modulation by various cancer chemoprophylaxis agents. Although miRNA therapeutics have been found to suppress gene expression effectively as compared to anti-sense oligonucleotide strategies, but it is bound with some limitations viz. identification of tissue specific miRNA, biological instability, off-target effects and delivery in the cell system. Up to certain extent, these hurdles have been resolved by chemical modifications using cholesterol conjugation, morpholinos, cationic lipids and cationic nanoparticles. Still more research is needed to understand the mechanism of action for better miRNA therapeutics. The paper discusses the potential miRNA therapeutics and diagnostic applications for cancer prevention, based on recent patents and their analysis.

Newer treatments of advanced human cancer are based on combination of cancer drugs that have different mechanism of actions yet the combination strategy may potentiate the anti-cancer effects and cytotoxicity. Recent studies suggest that cancer growth can be inhibited more effectively by combination of phytochemicals that affect different pathways. The apoptotic activity can be modulated by intrinsic and extrinsic molecules. The combination of anti-tumor phytochemicals can be more effective in modulating different signaling pathways associated with tumor cell growth which is the common target for anti-tumor action. Combinations of cytotoxic anti-tumor agents and inhibitors from phytochemicals are believed to act together producing inhibitory mechanisms on cancer growth. This combination strategy shows promise on cancer therapy. However, the combination of phytochemicals in cancer therapy needs to be further investigated to develop a better treatment strategy. Recent patents on anti-tumor phytochemicals are reviewed in this article.

The molecular hybridization (MH) is a strategy of rational design of such ligands or prototypes based on the recognition of pharmacophoric sub-units in the molecular structure of two or more known bioactive derivatives which, through the adequate fusion of these sub-units, lead to the design of new hybrid architectures that maintain pre-selected characteristics of the original templates. The concept of molecular hybridization and the promises/challenges associated with these hybrid molecules along with recent advances on anticancer hybrids and critical discussions on the future aspects of the hybrid drugs have already been presented through a number of reports. However, this article presents the structures of potent hybrids reported during the last two decades along with a detailed account of the patent literature. Significant number of patents on the molecules designed through this valuable drug design technique clearly highlight the present focus of the researchers all around the globe towards hybrid molecules capable of amplifying the effect of individual functionalities through action on another bio target or to interact with multiple targets as one single molecule lowering the risk of drug-drug interactions and minimizing the drug resistance. This review article basically emphasizes the patent literature along with an overview of potent hybrid structures, their IC50 /GI50 values against the various cell lines employed. The present compilation can be utilized as a guide for the medicinal chemists focusing on this area of drug design.

Resveratrol is a poly-phenol with many beneficial effects: not only as an antioxidant, anti-inflammatory, and antiatherogenic agent, as well as a platelet aggregation inhibitor, but also as an antiproliferative and proapoptotic factor in various types of cancers. There are reviews about the mechanisms responsible for its effects in leukemia and lymphomas, emphasizing the chemosensitizing role of resveratrol, which allows overcoming the multidrug resistance of cancers. The action of resveratrol occurs preferentially on leukemic cells, and not on the normal ones. In addition, it is one of the few drugs that act on leukemic stem cells. If experimental results are promising, its application in humans encounters some difficulties. The paper presents the causes of its low bioavailability, as well as recent patents that allow improvement of its bioavailability, development of new extraction procedures, obtaining new formulae, and associating resveratrol with other drugs in order to increase its effects. These patents allow optimizing its effects in order to obtain an adjuvant agent for treatment of oncohematological disorders.

Transforming growth factor beta (TGF-β) plays different roles in health and disease. TGF-β has been assumed as a dual factor in tumor growth, since it can repress epithelial tumor development in early stages, while it acts as a tumor promoter in the late stages of tumor progression. The cancer cells, during cancerogenesis, acquire migration and invasion capacities and finally they metastasize. The urokinase type plasminogen activator (uPA) system, comprised of uPA, the cell surface receptor (uPAR) and plasminogen-plasmin, is involved in the proteolytic degradation of the extracellular matrix and it also regulates several critical cellular events by its capacity to trigger the activation of intracellular signaling pathways. This enables the cancer cell survival, its dissemination, and enhancement of cell malignancy during tumor progression. The expression of both uPA and uPAR is finely regulated in normal development, but their expression is deregulated in cancer. TGF-β regulates uPA expression in cancer cells while uPA, by conversion of plasminogen to active form, plasmin, may release TGF-β from its latent state. Thus, these pathways cross-regulate each other by mutual feedback contributing to tumor progression. Here, we review the specific roles and the interplay between TGF-β and uPA system in cancer cells, the current cancer therapies and the novel patents focused mainly on uPA and TGF-beta ligands and their cell surface receptors respectively. Finally, with regard to the mutual activity of uPA and TGF-β in tumorigenesis, the aim of this review is to expose the potentiality of TGF-β and uPA systems as becoming combinatorial targets for therapies and patents.

The majority of patients with lung cancer present with advanced stage which contributes to death of more people than any other malignancy in the world. The discovery of a number of lung cancer-molecular alterations contributes to uniquely targeted therapies with specific inhibitors for non-small cell lung cancer such as erlotinib, gefitinib and crizotinib. Pemetrexed has statistically shown significantly reduced adverse side effects of drug compared with docetaxel. V1801, an analog of gefitinib may overcome gefitinib resistance in patients with non-small cell lung cancer. Thymosin α1, an immunomodulator significantly improves patient’s quality of life by enhancing T-cell function, stimulation of Tcell maturation and differentiation. Various novel compounds and chemotherapeutics were introduced in 2013 patents such as taxane, quinazoline, arylamino purine, benzodiazepine, pyrrolopyrimidine, nitrobenzamide, cyclopropane amide, 4-iodo-3-nitrobenzamide, heteroaryl (alkyl) dithiocarbamate, and histone deacetylase in treating non-small-cell lung cancer and piperidine, piperazine, picoplatin, and arsenic trioxide in treating small-cell lung cancer.

Afatinib is a recently introduced new tyrosine kinase inhibitor, approved by the USFDA on July 12, 2013. Afatinib is marketed under the trade name Gilotrif and developed by Boehringer Ingelheim GmbH. It is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) carrying EGFR exon 19 deletions or exon 21 (L858R) mutations. Afatinib is a covalent, irreversible inhibitor of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and HER4. Chemically afatinib is a 4-anilinoquinazoline derivative, having an acrylamide warhead. Gilotrif is the formulation of Afatinib di-meleate salt. Presently, afatinib has been approved in the USA, the European Union, Taiwan and Mexico. In this review, we have summarized the chemical characterization of afatinib, its synthesis, patent status, marketed formulation, available crystalline form and current clinical trials.