Recent Patents on Anti-Cancer Drug Discovery - Volume 10, Issue 1, 2015

Cancer stem cells (CSCs) refer to a subset of tumor cells with the potential to self-renew and differentiate into different cancer subtypes, including leukemias and solid tumors. Dysregulated gene expression and alteration of critical signaling pathways have been observed in CSCs, compared to low-tumorigenic bulk tumor cells. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, recurrence, distant metastasis, angiogenesis, and drug/radiation resistance. In recent years, CSCs have attracted a great deal of attention due to the remarkable potential for the development of specific therapies targeting CSCs and the identification of key molecules that play a critical role in controlling the unique features of CSC-enriched populations. During the last several years, a tremendous amount of work has been done on developing new drugs and therapeutic products, such as small molecule inhibitors, antibodies, and small interfering RNAs (siRNAs). These CSC-targeting agents selectively inhibit key components of various intrinsic signaling pathways or specific cell surface markers of CSCs. Many novel therapeutic agents and new molecular targeting compounds have been tested, some of which are currently under investigation in preclinical and clinical trials. In this review article, we provide an overview of the current status of the CSC hypothesis and discuss the various critical signaling pathways and specific cell surface markers involved in the development and maintenance of CSC populations. In addition, we also review various patents and CSC-targeting therapeutic strategies that may eventually lead to eradication of both bulk tumor cells and CSCs.

Pyrimidine ring is the building unit of DNA and RNA and thus pyrimidine based chemical architectures exhibit diverse pharmacological activities. Among the reported medicinal attributes of pyrimidines, anticancer activity is the most extensively reported. The anticancer potential of pyrimidines in fused scaffolds has also been evidenced through number of research article and patent literature. The pyrimidines based scaffolds have exerted their cell killing effects through varied mechanisms which indicate their potential to interact with diverse enzymes/ targets/receptors. This review article strictly focuses on the patent literature from 2009 onwards. The structure of the potent compounds, their IC50 values, models/assays used for the anticancer evaluation and the enzymes/ receptors/ targets involved have been presented in this compilation. Significant number of patents i.e. 59 have been published on pyrimidine based anticancer agents from 2009-2014 (from 2009 through the present date) which clearly indicate that this heterocycle is an area of focus at present for researchers all over the globe. Moreover, out of the 59 patents published during this period, 32 have been published from 2012 onwards which further highlights the present interest of the researcher towards pyrimidine based anticancer agents. The promising activity displayed by these pyrimidine based scaffolds clearly places them in forefront as potential future drug candidates. The present compilation can be extremely beneficial for the medicinal chemists working on design and synthesis of anticancer drugs.

Medicines developed from traditional systems are well known for their various important pharmaceutical uses. Cancer has been known since ancient times and has been mentioned in the ancient Ayurvedic books. Thus natural based products play a significant role in cancer chemotherapeutics. Further, approximately 70% of anticancer compounds are based on natural products or have been derived from their structural scaffolds. Hence, there is a growing interest for developing medicines from these natural resources. Amongst the methods of treating cancer, therapies targeting cancer stem cell are found to control metastatic tumor which is a newly identified factor associated with relapse. This patent review aims to highlight the use of natural products to treat cancer by targeting the cancer stem cells. The review will also provide insights into the reported mechanisms by which the natural products act in order to suppress or kill cancer stem cells. The analysis has been done using various criteria such as the patenting trend over the years, comparison of active assignee and a comparison of the technical aspects as disclosed in the different patent documents. The analysis further highlights different bioactives, the scaffolds of which could thus be a promising candidate in the development of anti-cancer drugs by targeting the cancer stem cells. The technical aspects covered in this review include: Bioactives and formulations comprising the extracts or bioactives, their mode of action and the type of assay considered to study the efficacy of the natural products. Further the mapping has helped us to identify potential therapeutic areas to evaluate herbs/bioactives and their uses for developing new formulations.

Oral delivery of poorly bioavailable therapeuticals is challenging. The challenges are more serious when physiological factors of gut such as cytochrome P450, P-glycoprotein, permeability, pH triggered precipitation and degradation are responsible for poor bioavailability. P-Glycoprotein mediated multidrug resistance is on high agenda for anti-cancer drugs. The present article compiled different methodologies used to curb these challenges of bioavailability. The concepts of poor bioavailability are illustrated along with possible management. Numerous relevant patents for bioavailability enhancement are also highlighted. Though, there is no universal approach for bioavailability enhancement, the drug related challenges are managed by altering its physicochemical characteristics or employing formulation technology, while the effects of physiological factors are minimized by using efflux transport inhibitor or cytochrome P-450 inhibitor or prodrug or through formulation technologies (enteric coating or microenvironment of pH etc.).

Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489).

Alteronol, isolated from microbial mutation strains, has been applied for Chinese and International patents for tumor treatment. The aim of this project study is to investigate characteristics of proliferation and redifferentiation induced by alteronol in B16-F0 mouse melanoma cells. Cell proliferation is determined by tetrazolium salt colorimetric method (MTT assay). Morphological changes were analyzed by using Giemsa staining. The levels of melanin and tyrosinase were measured by spectrophotometry. The mRNA expressions of tyrosinase-related protein Trp1 and Trp2 were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The anchorage-independent proliferation of B16-F0 was monitored by the colony formation assay. Tumorigenicity was characterized by an animal model in vivo. The results showed that the proliferation of B16-F0 cells was inhibited by alteronol in a concentration and time dependent manner. All well-known evaluation indexes of melanoma cell differentiation, including morphological changes and tyrosinase activity alteration, were greatly enhanced with the increase of alteronol concentrations. Taken together, the expression of tyrosinase related gene, decreased cell colony formation rate and the tumorigenicity in vivo; all of these revealed that alteronol plays a key role in inducing differentiation and suppressing the proliferation of B16-F0 tumor cells in vitro and in vivo.