Therapeutic targeting of B7-H1 in breast cancer

Introduction: Breast cancer is the most common form of malignancy occurring in women worldwide. B7-H1 is a co-inhibitory molecule expressed by several types of tumors, including breast cancer. The aberrant expression of B7-H1 in breast cancer cells has been determined, its role in recruiting regulatory T cells into the tumor microenvironment has been elucidated and a strong link to B7-H1 induction in highly proliferative breast cancer has been provided. It has also been demonstrated that doxorubicin, a drug commonly used for breast cancer treatment, downregulates the cell surface expression of B7-H1 and upregulates its nuclear expression, which therefore suggests an anti-apoptotic role of B7-H1 in breast cancer.

Areas covered: This review illustrates the various factors involved in the induction of B7-H1 and its role in immune evasion and chemoresistance. It also provides potential therapeutic strategies for targeting B7-H1 in breast cancer.

Expert opinion: B7-H1 should be considered as a potential therapeutic target for breast cancer. Indeed, there is increasing evidence for the potential efficacy of B7-H1 blockade in the prevention of immune evasion by cancer cells. Additionally, B7-H1 targeting can be used in conjunction with other therapeutic modalities for improved efficacy and reduced toxicity. We expect that B7-H1 blockade in combination with other therapeutics will be a prime therapeutic strategy in the future.     

Resveratrol derivatives: an updated patent review (2012-2015)

Introduction: Resveratrol is a well-studied natural small molecule that possesses diverse bioactivities. Chemical derivation based on the resveratrol scaffold is of great importance to overcome the drawbacks of resveratrol and to improve its therapeutic potential. Continuous efforts have been established to develop resveratrol derivatives that target different therapeutic applications.

Areas covered: This review covers patents published from 2012 to 2015. All resveratrol derivatives discussed are classified based on its derivation strategy as simple derivatives, conjugated derivatives and miscellaneous derivatives. Their therapeutic related activities are reviewed and discussed.

Expert opinion: Chemical derivation is an effective strategy to enhance the benefits of resveratrol and ameliorate its disadvantages. Recent studies on resveratrol derivatives have made great progress in the treatment of cancer and neurodegenerative diseases to name a few, demonstrating improved activity compared with resveratrol. Notably, its bioavailability was also improved in some cases. However, the ‘next generation’ of resveratrol derivatives still requires the development of new strategies and techniques.     

Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010 – 2014)

Introduction: The proteolytic activity of neutrophil elastase (NE) not only destroys pathogens but also degrades host matrix tissues by generating a localized protease–antiprotease imbalance. In humans, NE is well known to be involved in various acute and chronic inflammatory diseases, such as chronic obstructive pulmonary disease, emphysema, asthma, acute lung injury, acute respiratory distress syndrome and cystic fibrosis. The regulation of NE activity is thought to represent a promising therapeutic approach, and NE is considered as an important target for the development of novel selective inhibitors to treat these diseases.

Areas covered: This article summarizes and analyzes patents on NE inhibitors and their therapeutic potential based on a review of patent applications disclosed between 2010 and 2014.

Expert opinion: According to this review of recent NE inhibitor patents, all of the disclosed inhibitors can be classified into peptide- and non-peptide-based groups. The non-peptide NE inhibitors include heterocyclics, uracil derivatives and deuterium oxide. Among the heterocyclic analogs, derivatives of pyrimidinones, tetrahydropyrrolopyrimidinediones, pyrazinones, benzoxazinones and hypersulfated disaccharides were introduced. The literature has increasingly implicated NE in the pathogenesis of various diseases, of which inflammatory destructive lung diseases remain a major concern. However, only a few agents have been validated for therapeutic use in clinical settings to date.     

Cathepsin B and L inhibitors: a patent review (2010 - present)

Introduction: Cathepsins play an important role in protein degradation and processing. Aberrant cathepsin B or L is closely associated with many serious diseases such as cancer, osteoporosis and autoimmune disorders. Therefore, development of potent and selective cathepsin B and L inhibitors has aroused much attention in recent years. Although several classes of cathepsin inhibitors are presently available, there are still some problems to solve, such as broad-spectrum inhibition to protease, specially cysteine proteases, which lead to unpredictable side effects in clinical trials. Therefore, it is very necessary to discovery new scaffolds and new application of cathepsin B and L inhibitors for developing therapeutic agents for treating diseases mediated by cathepsin B or L.

Areas covered: This updated review summarizes new patents on cathepsin B and L inhibitors from 2010 to present.

Expert opinion: The review gives the latest development in the area of inhibitors of cathepsin B and L, which have been considered key therapeutic targets for the development of drugs treating related diseases. This review puts emphasis on the discovery of novel small molecule inhibitors of cathepsin B and L, as well as their new application as new therapeutic agents.     

Eribulin mesylate for the treatment of breast cancer

Importance of the field: Breast cancer is the most common cause of cancer-related death among women in the USA, and additional effective and well-tolerated chemotherapeutic agents are urgently needed. Eribulin mesylate (E7389), a synthetic analog of the marine macrolide halichondrin B, is a microtubule inhibitor with a unique tubulin binding site and mechanism of action.

Areas covered in this review: Based on a review of the literature between 2005 and 2010, we present a summary of eribulin and its clinical activity, specifically in metastatic breast cancer.

What the reader will gain: The mechanism of action of eribulin, preclinical data indicating antitumor activity of eribulin and data from Phase I and II clinical trials evaluating the efficacy and tolerability of eribulin are presented.

Take home message: Based on data from Phase I and II clinical trials, we conclude that eribulin seems to have efficacy in metastatic breast cancer, even among women with heavily pretreated and taxane-resistant disease. In addition, eribulin has a manageable side-effect profile, consisting mainly of neutropenia and fatigue, and most notably a low incidence of peripheral neuropathy. With these encouraging results, additional Phase II and III studies are ongoing. Eribulin seems to be a promising new agent for the treatment of metastatic breast cancer.     

Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016)

Introduction: Ursolic acid (UA), belongs to a group of pentacyclic triterpenoids and is known to possess some very interesting biological properties. Protocols have been developed in order to synthesize bioactive UA analogs which have resulted in numerous ursolic acid analogs being synthesized during the period 2012–2016. Ursolic acid and its analogues can be employed to treat various cancers, inflammatory diseases, diabetes, Parkinson’s disease, Alzheimer’s disease, hepatitis B, hepatitis C and AIDS to mention but a few.

Areas covered: This review covers patents on therapeutic activities of ursolic acid (UA) and its synthetic derivatives published during the four year period 2012–2016. A discussion about structure-activity relationships (SAR) of these analogs is also included.

Expert opinion: Ursolic acid and its synthetic derivatives demonstrated excellent anticancer, antidiabetic, antiarrhythmic, anti-hyperlipidemic, antimicrobial, anti-hypercholesterolemic, and anti-cardiovascular properties. Additionally, various ursolic acid analogues have been synthesized through modification at positions C₂-OH, C₃-OH and C_17-CO₂H. It is noteworthy that the C-17 amide and amino analogs of UA possessed better anticancer activity compared to the parent compound (UA). Most importantly, UA has the potential to conjugate with other anticancer drugs or be transformed into its halo derivatives since this will greatly facilitate scientists to get lead compounds in cancer drug discovery.     

Oxazolidinone antimicrobials: a patent review (2012-2015)

Introduction: Antimicrobial resistance in Gram-positive bacteria is a major health care issue. This review summarizes patent publications from 2012 to 2015 that divulged novel oxazolidinones as antibacterial agents.

Areas covered: A total of 25 patents obtained from Espacenet, WIPO Patentscope and FreePatentsOnline, and AcclaimIP search engines were reviewed. The patents were scrutinized based on the novelty of the compounds, their antibacterial activity (MIC, µg/mL), and the process of preparation. The oxazolidinones with promising antibacterial activity were classified according to the following structural diversities, as biaryl heterocyclic, fused heteroaryl rings containing oxazolidinones, and others. The biaryl heterocyclic, fused heteroaryl, benzoxazine, and the 1H-pyrazol-1-yl containing oxazolidinone derivatives demonstrated potent antibacterial activities superior to linezolid against Gram-positive bacteria. Some derivatives were effective against standard strains of Gram-negative bacteria, namely Moraxella catarrhalis ATCC A894, and Escherichia coli ATCC 25922. In addition, a patent disclosed a structural isomer of linezolid with marginal activity against the aerobic Gram-negative bacteria MDR Stenotrophomonas (Xanthomonas) maltophilia, while linezolid and vancomycin did not inhibit growth. Finally, some derivatives showed activity against respiratory infectious diseases’ causative agents, such as B. anthracis, B. mallei, Y. pestis, and M. pneumoniae.

Expert opinion: Overall, there is limited in vivo data to support the potential clinical advancement of the currently reported novel derivatives.     

2-Indolinone a versatile scaffold for treatment of cancer: a patent review (2008–2014)

Introduction: 2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block.

Areas covered: The present review gives an account of the recent patent literature (2008–2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed.

Expert opinion: 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2-indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.     

Novel IκB kinase inhibitors for treatment of nuclear factor-κB-related diseases

Introduction: NF-κB is a key regulator of inflammation and immunity in cancer development. The IκB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -β and -γ. It is well known that many pro-inflammatory stimuli require the IKK-β subunit for NF-κB activation.

Areas covered: NF-κB affects the progression of inflammation-related diseases, such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases.

Expert opinion: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future.     

Resveratrol derivatives: a patent review (2009 – 2012)

Introduction: There is currently a wealth of information on the effects of resveratrol and its derivatives in therapeutic, cosmetic and nutraceutical patent applications. Structure–activity studies of the resveratrol scaffold provide a foundation for the development of new analogs with potent activity or other beneficial properties. Ongoing research has yielded promising results and potential use in the treatment of various diseases.

Areas covered: This review provides analysis of patents published from January 2009 to April 2013. There is a focus on different approaches for the production of resveratrol derivatives, combinations of new derivatives with old drugs, and applications in therapeutic areas, nutraceutical compositions and cosmetics.

Expert opinion: The ability of resveratrol to interact with a disparate array of subcellular targets is uncanny. Nonetheless, even though limited or no toxicity is apparent, the molecule is not a panacea due to lack of potency and issues with bioavailability. Thus, as witnessed by a number of patents, a large assortment of derivatives have been synthesized under the guise of having superior characteristics for treating or preventing various diseases or for use as neutraceutics and cosmetics. Some of these suppositions are probably correct, but evidence-based applications are essentially nil due to a lack of commitment in terms of investing the resources necessary for the conduct of obligatory clinical trials. Current usage is largely based on anecdotes and publicity. Hopefully, at some point in time, it will be possible to follow a standard protocol with a predicable outcome.     

Therapeutic effects of EGCG: a patent review

Introduction: Green tea contains polyphenolic flavanoids such as epigallocatechin-3- gallate (EGCG), epicatechin-3-gallate (ECG), epigallocatechin (EGC) and epicatechin (EC). EGCG is the most abundant and active compound in green tea. Extensive research has shown that it has significant antioxidant, anti-carcinogenic, anti-microbial, and neuroprotective properties and has therapeutic potential against various human diseases.

Areas covered: This review focuses on the applications of EGCG alone, and in combination with other compounds, for the treatment of various types of cancers, metabolic, neurodegenerative, and microbial diseases, and discusses its mechanism of action in cell line and animal modesl. Recent advances, which include the use of nanoencapsulated EGCG to enhance the drug delivery and reduce cell toxicity, have also been discussed along with the comprehensive analysis of the specific granted patents associated with EGCG.

Expert opinion: Under the current scenario, the role of EGCG as a therapeutic agent is being utilised and new approaches are being formulated to overcome the problem of stability and bioavailability of EGCG. EGCG and its derivatives could be used for the development of drugs for the treatment of cancer, as well as various microbial, metabolic, and neurodegenerative diseases.     

Chloroquine-containing compounds: a patent review (2010 – 2014)

Introduction: Chloroquine (CQ) has been well known for its antimalarial effects since World War II. However, it is gradually being phased out from clinical use against malaria due to emergence of CQ-resistant Plasmodium falciparum strains. Besides low cost and tolerability, ongoing research has revealed interesting biochemical properties of CQ that have inspired its repurposing/repositioning in the management of various infectious/noninfectious diseases. Consequently, several novel compounds and compositions based on its scaffold have been studied and patented.

Areas covered: In this review, patents describing CQ and its derivatives/compositions over the last 5 years are analyzed. The review highlights the rationale, chemical structures, biological evaluation and potential therapeutic application of CQ, its derivatives and compositions.

Expert opinion: Repurposing efforts have dominantly focused on racemic CQ with no studies exploring the effect of the (R) and (S) enantiomers, which might potentially have additional benefits in other diseases. Additionally, evaluating other similarly acting antimalarials in clinical use and structural analogs could help maximize the intrinsic value of the 4-aminoquinolines. With regard to cancer therapy, successful repurposing of CQ-containing compounds will require linking the mode of action of these antimalarials with the signaling pathways that drive cancer cell proliferation to facilitate the development of a 4-amino-7-chloroquinoline that can be used as a synergistic partner in anticancer combination chemotherapy.     

Pharmacological effects of berberine and its derivatives: a patent update

Introduction: A number of plant-derived agents are used in many therapeutic areas. Berberine, an important protoberberine alkaloid, is present in a number of medicinal plants that have been widely used in traditional Chinese medicine for hundreds of years. Modern research has shown that berberine and its derivatives display several pharmacological effects through various mechanisms.

Areas covered: This review discusses recent and mostly Chinese patents that report the synthesis of berberine, berberine derivatives and berberine salts, and methods of preparation for formulations (traditional Chinese medicine) containing herbal components rich in berberine, along with their applications. The review covers several therapeutic effects of berberine, its derivatives and pharmaceutical formulations against cancer, obesity, diabetes, inflammation, atherosclerosis, Alzheimer’s disease, rheumatoid arthritis and cardiovascular diseases. In addition, the mechanisms underlying the pharmacological effects are discussed.

Expert opinion: Modification of the functional groups of berberine has a significant effect on the pharmacological activity. However, studies on altering the atoms and size of the berberine skeleton are rare. Thus, it may be beneficial to initiate a drug development program focused on inserting heterocyclic rings of different sizes into berberine. Furthermore, structural modification to improve the safety, efficacy and selectivity is necessary to promote the use of berberine-based drugs in clinical settings.     

Therapeutic potential of boswellic acids: a patent review (1990-2015)

Introduction: Boswellic acids (BAs), a group of pentacyclic triterpenoids, have demonstrated very interesting biological properties that resulted in a number of protocols being developed for their synthesis. During the last twenty-five years (1990–2015), numerous BAs have been prepared. Both natural BAs and their synthetic derivatives can be used to treat various cancers as well as inflammatory diseases.

Areas covered: This review covers patents on therapeutic activities of natural BAs and their synthetic derivatives published in last twenty-five years (1990–2015). Only BA patents to treat cancer and inflammation are available. A discussion about structure-activity relationships (SAR) of these analogs is also included.

Expert opinion: BAs possess excellent anticancer and anti-inflammatory properties. A large number of BAs and their analogues have been prepared through modification at the C₃-OH and C₂₄-CO₂H functional groups. Most importantly, the C-24 amide and amino derivatives demonstrated increased anticancer and anti-inflammatory activity compared with other BA derivatives. Furthermore, BAs have the potential to form conjugates with other anticancer drugs that will synergistically enhance their anticancer effects; and we believe that in order to get lead compounds, there needs to be a greater focus on the synthesis of halo derivatives of BAs.     

Targeting silibinin in the antiproliferative pathway

Importance of the field: Due to the failure and severe toxicity of cancer chemotherapy, silibinin, a natural flavonoid from the seeds of milk thistle, has recently received more attention for its potential anticancer and nontoxic roles in animals and humans. Silibinin has clearly demonstrated inhibition of multiple cancer cell signaling pathways, including growth inhibition, inhibition of angiogenesis, chemosensitization, and inhibition of invasion and metastasis. Cumulative evidence implicates that silibinin is a potential agent for cancer chemoprevention and chemotherapy.

Areas covered in this review: Our aim is to discuss the recent progress of silibinin in regulating multiple anticancer proliferative signaling pathways; the review covers literature mainly from the past 3 – 5 years.

What the reader will gain: One of the strategies for tumor therapy is eradication of cancer cells through targeting specific cell-proliferative pathways. This review highlights the current knowledge of silibinin in regulating multiple cellular proliferative pathways in cancer cells, including receptor tyrosine kinases, androgen receptor, STATs, NF-κB, cell cycle regulatory and apoptotic signaling pathways.

Take home message: The molecular mechanisms of silibinin-mediated antiproliferative effects are mainly via receptor tyrosine kinases, androgen receptor, STATs, NF-κB, cell cycle regulatory and apoptotic signaling pathways in various cancer cells. Targeting inhibition of proliferative pathways through silibinin treatment may provide a new approach for improving chemopreventive and chemotherapeutic effects.     

Novel aldose reductase inhibitors: a patent survey (2006 – present)

Introduction: Initially studied for its central role in the pathogenesis of chronic diabetic complications, aldose reductase (ALR2) gains more attention over the years as its implication in inflammatory diseases is being established, along with the therapeutic potential of its inhibitors.

Areas covered: Reviewing the patents that were published since 2006, it is getting clear that the search for new chemical entities has subsided, giving rise to natural products and plant extracts with ALR2 inhibitory activity. Other aspects that were prominent were the search for proper forms of known inhibitors, in a way to improve their impaired physicochemical profile, as well as potential combination therapies with other compounds of pharmaceutical interest. On the spotlight were patents enhancing the therapeutic usage of aldose reductase inhibitors (ARIs) to various pathological conditions including cancer and inflammation-mediated diseases such as sepsis, asthma, and cancer.

Expert opinion: Although new chemical entities are scarcely registered and patented after many years of inconclusive clinical trials, the involvement of ALR2 to inflammatory pathologies might renew the interest in the field of ARIs.     

Fulvestrant: a unique antiendocrine agent for estrogen-sensitive breast cancer

Importance of the field: The role of estrogen deprivation for the treatment of breast cancer has been understood since the 1800s. Pharmacologic advances in the field in the past decades, including tamoxifen and the aromatase inhibitors, have contributed significantly to the reduced mortality of estrogen-sensitive breast cancer. However, this subtype of breast cancer still presents with relapses and, once metastatic, progression to hormone-refractory state and loss of disease control remain an expected disease course. Fulvestrant, a pure estrogen receptor downregulator, is a new addition to the antiestrogen therapeutic armamentarium since its FDA approval in 2002. Its unique mechanism of action offers potential advantages over other estrogen targeted therapies.

Areas covered in this review: Published scientific literature, including presented abstracts, on fulvestrant from 1985 to the present were reviewed with selected publications included.

What the reader will gain: This review addresses current issues and therapies for estrogen-sensitive breast cancer, highlights the role of fulvestrant in current treatment guidelines and outlines some of the ongoing investigations of this compound.

Take home message: Fulvestrant is an effective and well-tolerated drug for treatment of metastatic estrogen-sensitive breast cancer. Work is underway to enhance its clinical benefit to patients as a single agent and in combination with other therapies.     

Farnesyl pyrophosphate synthase modulators: a patent review (2006 – 2010)

Introduction: Farnesyl pyrophosphate synthase (FPPS, also known as farnesyl diphosphate synthase (FDPS)) is one of the key enzymes involved in the mevalonate pathway and as such is widely expressed. FPPS modulators, specifically FPPS inhibitors, are useful in treating a number of diseases, including bone-related disorders characterized by excessive bone resorption, for example, osteoporosis, cancer metathesis to bone and infectious diseases caused by certain parasites.

Areas covered: This review covers structures and applications of novel FPPS modulators described in the patent literature from 2006 to 2010. Patents disclosing new formulations and uses of existing FPPS inhibitors are also reviewed. Thirty-three patents retrieved from the USPTO, EP and WIPO databases are examined with the goal of defining current trends in drug discovery related to FPPS inhibition, and its therapeutic effects.

Expert opinion: Bisphosphonates (BPs) continue to dominate in this area, although other types of modulators are making their appearance. Remarkable for their high bone mineral affinity, BPs are structural mimics of the dimethylallyl pyrophosphate substrate of FPPS, and constitute the major type of FPPS inhibitor currently used in the clinic for treatment of bone-related diseases. Lipophilic BPs and new classes of non-BP FPPS inhibitors (salicylic acid and quinoline derivatives) have been introduced as possible alternatives for treatment of soft tissue diseases, such as some cancers. Novel formulations, fluorescent diagnostic probes and new therapeutic applications of existing FPPS inhibitors are also areas of significant patent activity, demonstrating growing recognition of the versatility and underdeveloped potential of these drugs.     

Emerging MEK inhibitors

Importance of the field: The Ras/Raf/MEK/ERK pathway is often activated by genetic alterations in upstream signaling molecules. Integral components of this pathway such as Ras and B-Raf are also activated by mutation. The Ras/Raf/MEK/ERK pathway has profound effects on proliferative, apoptotic and differentiation pathways. This pathway can often be effectively silenced by MEK inhibitors.

Areas covered by this review: This review will discuss targeting of MEK which could lead to novel methods to control abnormal proliferation which arises in cancer and other proliferative diseases. This review will cover the scientific literature from 1980 to present and is a follow on from a review which focused on Emerging Raf Inhibitors published in this same review series.

What the reader will gain: By reading this review the reader will understand the important roles that genetics play in the response of patients to MEK inhibitors, the potential of combining MEK inhibitors with other types of therapy, the prevention of cellular aging and the development of cancer stem cells.

Take home message: Targeting MEK has been shown to be effective in suppressing many important pathways involved in cell growth and the prevention of apoptosis. MEK inhibitors have many potential therapeutic uses in the suppression of cancer, proliferative diseases and aging.