A patent update on PDK1 inhibitors (2015-present)

Introduction: 3-Phosphoinositide-dependent kinase 1 (PDK1), the ‘master kinase of the AGC protein kinase family’, plays a key role in cancer development and progression. Although it has been rather overlooked, in the last decades a growing number of molecules have been developed to effectively modulate the PDK1 enzyme.

Areas covered: This review collects different PDK1 inhibitors patented from October 2014 to December 2018. The molecules have been classified on the basis of the chemical structure/type of inhibition, and for each general structure, examples have been discussed in extenso.

Expert opinion: The role of PDK1 in cancer development and progression as well as in metastasis formation and in chemoresistance has been confirmed by many studies. Therefore, the pharmaceutical discovery in both public and private institutions is still ongoing despite the plentiful molecules already published. The majority of the new molecules synthetized interact with binding sites different from the ATP binding site (i.e. PIF pocket or DFG-out conformation). However, many researchers are still looking for innovative PDK1 modulation strategy such as combination of well-known inhibitory agents or multitarget ligands, aiming to block, together with PDK1, other different critical players in the wide panorama of proteins involved in tumor pathways.     

Screening methods for AMP-activated protein kinase modulators: a patent review

Introduction: AMP-activated protein kinase (AMPK) functions as a cellular energy gauge that maintains cellular homeostasis and has been suggested to play important roles in tumorigenesis, lifespan and autophagy. Accordingly, AMPK is a potential target of drugs for controlling a growing number of human diseases ranging from metabolic disorders to cancer, highlighting the need for rational and robust screening systems for identifying compounds that modulate AMPK.

Areas covered: The relevant screening methods in the patent and scientific literature were analyzed, and key features of direct AMPK modulators are discussed in the context of their physiological relevance and the three-dimensional structure of the AMPK complex.

Expert opinion: The mechanism of action of modulators is important in designing drugs with enhanced efficacy, specificity and stability. Most patented assay formats for identifying AMPK modulators are based on classical enzyme assays that monitor AMPK activity or changes in AMPK-dependent cellular physiology. However, these systems do not provide information about underlying mechanisms. Two patented assay systems use a specific domain or the three-dimensional structure of AMPK to identify AMPK modulators. The recent identification of two AMPK modulators, A-769662 and C-2 (or its prodrug, C-13), suggests the promise of structure-based assays in discovering more potent and specific modulators of AMPK.     

MYC modulators in cancer: a patent review

Introduction: The important role of MYC in tumorigenesis makes it particularly important to design MYC modulators. Over the past decade, researchers have raised a number of strategies for designing MYC modulators, some of which are already in clinical trials. This paper aims to review the patents of MYC modulators.

Areas covered: The important biological relevance of c-MYC and the regulation pathways related to c-MYC are briefly introduced. Base on that, the MYC modulators reported in published patents and references primarily for cancer treatment are outlined, highlighting the structures and biological activities.

Expert opinion: There has been a growing awareness of finding and designing MYC modulators as novel anticancer drugs over recent years. Patents involving the discovery, synthesis, and application of MYC modulators are particularly important for further development in this field. Although finding direct MYC inhibitors or binders is challenging, MYC cannot be simply defined as an undruggable target. There is still substantial evidence proving the concept that MYC modulators can benefit to the treatment of both human hematological malignancies and solid tumors. More efforts should be taken to improve the activity and specificity of MYC modulators.     

Novel pharmacological modulators of autophagy: an updated patent review (2012-2015)

Introduction: Autophagy is a lysosome-dependent degradation pathway that maintains cellular homeostasis in response to a variety of cellular stresses. Accumulating reports based on animal models have indicated the importance of this catabolic program in many human pathophysiological conditions, including diabetes, neurodegenerative diseases, aging, and cancers. Therefore, autophagy has been highlighted as a novel therapeutic target with a wide range of beneficial effects on human diseases. Here, we review the recent advances of our knowledge toward autophagy, as well as the efforts for developing autophagy modulators.

Areas covered: The relevant patents (published at 2012–2015) and the research literature claiming the pharmacological modulation of autophagy are reviewed. Also, their molecular mechanisms and potential therapeutic utilities are discussed.

Expert opinion: Considering the molecular machinery involved in autophagy induction, the targeting of autophagy-specific protein is very important to design the therapeutic interventions for specifically treating a variety of autophagy-associated disorders. Many patents and the research literature described in this review have shown promising applications of the relevant autophagy modulators for cancer or neurodegeneration treatments, a few of which are already being considered for clinical evaluation. However, most patents have claimed the modulators of autophagy with little information regarding their mechanisms of action. To design highly potent therapeutics, further work, such as developing compounds that specifically target the autophagy-specific machinery, are required.     

Mcl-1 inhibitors: a patent review

Introduction: The myeloid cell leukemia?1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. Therefore, there has been extensive research and development in the last decade in both academic and industrial settings to address this unmet medical need.

Areas covered: This review covers the research and patent literature of the past 10 years in the field of discovery and development of small-molecule inhibitors of the MCL-1 anti-apoptotic protein.

Expert opinion: Small-molecule strategies to disrupt the protein-protein interactions between MCL-1 and its pro-apoptotic counterparts, such as BAK and BIM, have recently emerged. Several small-molecules based on different scaffolds describe promising in vitro data as MCL-1 selective inhibitors. While many lead compounds remain at the in vitro preclinical development stage, the two most recent patent applications describe promising in vivo data, and one small molecule inhibitor has recently entered into clinical development. It is such an exciting moment that the long awaited clinical studies will generate some insight into the therapeutic potential of this anti-cancer approach, and possibly facilitate the further development of other early stage inhibitors.     

A FGFR1 inhibitor patent review: progress since 2010

Introduction: FGFR1 is a well known molecular target for anticancer therapy. Many studies have proved that the regulation of FGFR1 activity is a promising therapeutic approach to treat a series of cancers. Therefore, the development of potent inhibitors has consequently become a key focus in the present drug discovery, and it is encouraging that several highly selective FGFR1 inhibitors have been identified from various sources in recent years.

Areas covered: This article reviews patents and patent applications related to selective FGFR1 inhibitors published from 2010 to 2016. This summary highlights about 15 patents from different pharmaceutical companies and academic research groups. We used Baidu and NCBI search engines to find relevant patents as a search term.

Expert opinion: In the past few years, considerable progress has been made in the identification and development of selective FGFR1 inhibitors in use. At present, at least 10 inhibitors of FGFR1 are in clinical trials, and several agents have shown encouraging results under experimental conditions. Given the fact that FGFR1 plays a crucial role in the regulation of cancer and other diseases, we hope that it will gain further attraction from pharmaceutical companies and encourage development of more novel, safe and efficient FGFR1 inhibitors in the future.     

Protein kinase CK2 inhibitors: a patent review

Introduction: CK2 is a pleiotropic, ubiquitous and constitutively active protein kinase, localized in both cytosolic and nuclear compartments, where it catalyzes the phosphorylation of hundreds of proteins. CK2 is generally described as a tetramer composed of two catalytic (α and/or α′) and two regulatory subunits (β), however, the free α/α′ subunits are catalytically active by themselves. CK2 plays a key role in several physiological and pathological processes and has been connected to many neoplastic, inflammatory, autoimmune and infectious disorders. In the last 20 years, several inhibitors of CK2 have been discovered though only one of these, CX-4945, has recently entered into Phase II clinical trials as potential anticancer drug.

Areas covered: The main objective of the present review is to describe the development of CK2 activity modulators over the years according to the timeline of their patent registration.

Expert opinion: CK2 was discovered in 1954, but the first patent on CK2 modulators was deposited only 50 years later, in 2004. However, in the last 5 years an increasing number of patents on CK2 inhibitors have been registered, reflecting an increased interest in this kind of drug candidates and their possible therapeutic applications.     

Recent advances of pyrrolopyridines derivatives: a patent and literature review

Introduction: Several pyrrolopyridines or azaindoles have been reported in the literature as biologically-active molecules. Most of them are anticancer agents, and few possess other therapeutic effects.

Areas covered: The most recent biologically-active pyrrolopyridine derivatives have been reviewed from the patents and research articles published from 2010 to the mid of 2016. Their structural and biological features have been explained. In general, the pyrrolopyridine scaffold mimics the purine ring of the ATP molecule. So the well-designed pyrrolopyridine analogues can successfully act as kinase inhibitors for treatment of cancer and/or other diseases. The most successful pyrrolopyridine derivative that is currently used in the market is vemurafenib, which is used for treatment of melanoma. Its chemical and biological features have been reviewed and explained.

Expert opinion: The heterocyclic pyrrolopyridine nucleus mimics the purine ring of ATP. So they can work as inhibitors of the kinase at hinge region. Due to the structural similarity with ATP, these pyrrolopyridine derivatives are estimated to be non-selective kinase inhibitors. The selectivity is conferred mainly from the different substituents attached to the azaindole nucleus. More details are presented in the ‘Expert Opinion’ section at the end of this article. This section covers the chemistry and the biological properties of therapeutically-efficient pyrrolopyridine-possessing compounds.     

Adenosine A1 modulators: a patent update (2008 to present)

Introduction: In 2008, we published our review titled ‘Therapeutic potential of A₁ adenosine receptor ligands - a survey of recent patent literature' that reported the compounds active on A₁ adenosine receptors (ARs) and the applications of A₁ AR ligands patented in the period 2005 – 2008.

Areas covered: This article is a discussion of the patents about the same subjects, issued in the period 2008 to present. It is organized similarly to the first one, with a section about new compounds, subdivided on the basis of their functional activity (agonists, antagonists and allosteric modulators) and a section regarding new therapeutic applications.

Expert opinion: The main novelty is represented by the patenting of A₁ AR ligands with dual selectivity which may show, in some conditions, better efficacy and fewer side effects. Moreover, while the way to arrive into the market appears full of obstacles for selective A₁ ligands that need systemic administration for long-term therapy, better chances are foreseen in applications requiring topical administration.     

Bcr-Abl tyrosine kinase inhibitors: a patent review

Introduction: Breakpoint cluster region Abelson (Bcr-Abl) tyrosine kinase (TK) is a constitutively activated cytoplasmic TK and is the underlying cause of chronic myeloid leukemia (CML). To date, imatinib represents the frontline treatment for CML therapy. The development of resistance has prompted the search for novel Bcr-Abl inhibitors.

Areas covered: This review presents a short overview of drugs already approved for CML therapy and of the compounds that are in clinical trials. The body of the article deals with Bcr-Abl inhibitors patented since 2008, focusing on their chemical features.

Expert opinion: The search for Bcr-Abl inhibitors is very active. We believe that a number of patented compounds could enter clinical trials and some could be approved for CML therapy in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.     

Sigma receptor modulators: a patent review

Introduction: Sigma receptors are involved in several central nervous system (CNS) disorders, including mood disorders (depression and anxiety), psychosis, schizophrenia, movement disorders (i.e., Parkinson's disease) and memory deficits (i.e., Alzheimer's disease). Recently, the involvement of sigma receptors in neuropathic pain and cancer has also been observed.

Areas covered: This review aims at highlighting the research advancements published in the patent literature between 1986 and 2012, dividing patents according to both their time frame and applicants. The review especially focuses on the development of sigma receptor modulators and their application over the years with respect to CNS diseases, neuropathic pain and neurodegenerative pathologies. The literature was sought through Espacenet, Orbit, ISI Web and PubMed databases.

Expert opinion: In recent years, considerable progress in the knowledge of the biology and pharmacology of sigma receptors has encouraged research on the potential benefits of sigma modulators in a wide range of pathologies. So far, only few potent agonists and antagonists of sigma receptors are in clinical trial for acute and chronic neurodegenerative diseases (SA4503 and ANAVEX 2-73) or neuropathic pain (E-52862).     

Urate transporter URAT1 inhibitors: a patent review (2012 - 2015)

Introduction: Human urate transporter 1 (URAT1, encoded by SLC22A12) has been identified as a key urate transporter expressed at the apical membrane of renal proximal tubule cells for regulating urate homeostasis. Therefore, URAT1 is an attractive target for the development of new uricosurics against hyperuricemia. Discovery of novel inhibitors targeting URAT1 has become a research hotspot in recent years.

Areas covered: In this paper, we reviewed the patent applications and related research published during the years 2012–2015, covering the development of URAT1 inhibitors.

Expert opinion: There are some promising and inspiring patent applications in this area. Several compounds have superior inhibitory activity of URAT1 with the availability of urate-lowering treatment. For new drug development and commercialization, further studies are needed to evaluate the efficacy and safety.     

Sulfonamide inhibitors: a patent review 2013-present

Introduction: Sulfonamide compounds are significant class of synthetic bacteriostatic antibiotics still which used today for the therapy of bacterial infections and those caused by other microorganisms. They are also known as sulfa drugs and were the main source of therapy against bacterial infections before the introduction of penicillin in 1941. Additionally, The first sulfonamide section is present inmany clinically used drugs such as diuretics, carbonic anhydrase inhibitors and antiepileptics.

Areas covered in this review: The article presents the main classes of sulfonamide inhibitors investigated between 2013 and present. Specifically, the authors review the scientific and patent literature on tyrosine kinase, human immunodeficieny virus protease-1 (HIV?1), histone deacetylase 6, protein tyrosine phosphatase 1B, sphingosine kinase, phosphatidyl inositol 3-kinase, angiogenesis, pyrazole kinase, tyrosyl DNA phosphodiesterase inhibitors were evaluated.

Expert opinion: Sulfonamides are utilized as the antiviral HIV protease inhibitor amprenavir, as an anticancer agent, and in Alzheimer’s disease drugs. All these data show that although known for more than 100 years, the primary sulfonamides constitute an important class of compounds which leads to highly valuable drugs and drug candidates for many conditions, such as cancer, glaucoma, inflammation, dandruff, just to mention the most investigated ones.     

Analogs,formulations and derivatives of imatinib: a patent review

Introduction: The Bcr-Abl inhibitor imatinib was approved in 2001 for chronic myeloid leukemia therapy, and dramatically changed the lives of patients affected by this disease. Since it also inhibits platelet derived growth factor receptor (PDGFR) and c-Kit, imatinib is used for various other tumors caused by abnormalities of one or both these two enzymes.

Areas covered: This review presents an overview on imatinib formulations and derivatives, synthetic methodologies and therapeutic uses that have appeared in the patent literature since 2008.

Expert opinion: Innovative imatinib formulations, such as nanoparticles containing the drug, will improve its bioavailability. Moreover, oral solutions or high imatinib content tablets or capsules will improve patient compliance. Some solid formulations and innovative syntheses that have appeared in the last few years will reduce the cost of the drug, offering big advantages for poor countries. Some recently patented efficacious imatinib derivatives are in preclinical studies and could enter clinical trials in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.     

Novel GABAB receptor positive modulators: a patent survey

Importance of the field: Positive allosteric modulators of GABA_B receptors may have a similar potential as positive modulators of GABA_A receptors, the benzodiazepines discovered in 1957. The discovery of positive allosteric modulators of GABA_B receptors at Novartis in Basel in 2000 opened the way to search for compounds, which activate GABA_B receptors without the drawbacks of full agonists, such as desensitization, tolerance, muscle-relaxant effects, hypothermia, and central and gastrointestinal side effects.

Areas covered in this review: Numerous animal experiments point out that several indications can be addressed with positive modulators of GABA_B receptors, such as depression, anxiety, schizophrenia, neuropathic and chronic pain and treatment of craving for drugs of abuse, such as alcohol, cocaine and nicotine. Peripherally acting compounds may be valuable drugs for the treatment of gastroesophageal reflux disease and irritable bowel syndrome.

What the reader will gain: An overview on 19 patents in this field, of the different scaffolds for positive modulators of GABA_B receptors and of the major players in the field.

Take home message: The search for subtype selective benzodiazepine receptor ligands has proved to be extremely difficult. Positive modulators of GABA_B receptors may provide novel anxiolytic drugs faster.     

Anti-norovirus therapeutics: a patent review (2010-2015)

Introduction: Human noroviruses are the primary causative agents of acute gastroenteritis and are a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. An improved understanding of norovirus biology, as well as the pathogenic mechanisms underlying the disease, has provided the impetus for a range of intense exploratory drug discovery efforts targeting viral and host factors.

Areas covered: An overview of norovirus inhibitors disclosed in the patent literature (2010-present) and Clinicaltrials.gov is presented. The review is further enriched and supplemented by recent literature reports.

Expert opinion: Seminal discoveries made in recent years, including a better understanding of the pathobiology and life cycle of norovirus, the identification and targeting of multiple viral and host factors, the advent of a replicon system and a small animal model for the preclinical evaluation of lead compounds, and the availability of high resolution X-ray crystal structures that can be utilized in structure-based drug design and lead optimization campaigns, collectively suggest that a small molecule therapeutic and prophylactic for norovirus infection is likely to emerge in the not too distant future.     

LSD1 inhibitors: a patent review (2010-2015)

Introduction: Lysine demethylase 1 (LSD1) plays an important role in mediating the expression of genes involved in cancer and non-cancer diseases such as viral infections, cardiovascular and neurodegenerative disorders. It is involved in a number of processes from adipogenesis to cell adhesion to viral latency, regulating several cell pathways related with proliferation, development, and cell cycle control. Numerous chemical entities have been studied in recent years and some of them entered the clinical arena.

Areas covered: This review summarizes recent efforts in the drug development of LSD1 inhibitors reported in the patent literature covering the 2010-2015 period, including their potential use as therapeutics in cancerous, neurological, inflammatory, cardiovascular, and viral diseases.

Expert opinion: The development of novel potent and selective LSD1 inhibitors is ongoing, in order to improve their potency and selectivity against specific types of cancer or non-cancer diseases. More in-depth studies are required to assess the role of LSD1 inhibitors in the expression of LSD1 target genes, for a better assessment of the biochemistry underlying their efficacy, and to provide evidence for any possible side effects. Furthermore, an interesting therapeutic approach is the use of LSD1 inhibitors in conjunction with other epidrugs to combine their therapeutic potential, leading to innovative, personalized treatments.     

Farnesoid X receptor modulators: a patent review

Importance of the field: The farnesoid X receptor (FXR) is a key regulator of cholesterol homeostasis, triglyceride synthesis and lipogenesis. Given some patients' inability to tolerate existing medications, such as the statins, for cholesterol reduction, there is a pressing need for additional medicines to treat dyslipidemia. FXR agonists have emerged in discovery and preclinical efforts to show great potential for the treatment of these and other life-impairing and life-threatening conditions.

Areas covered in this review: Recent advances in the search for novel FXR modulators are reviewed, with a particular focus on patent applications and peer-reviewed publications disclosed in the past 5 years.

What the reader will gain: A total of 72 patent applications and peer-reviewed articles, containing 16 generic structure classes with nearly 5000 novel synthesized structures are reviewed. Where possible, the structure–activity relationship of these structure classes is surveyed, new insights into in vitro and in vivo efficacy of FXR agonists are disclosed, and potential new and promising therapeutic applications are revealed.

Take home message: FXR agonists have proven their efficacy and safety in primates and have significant potential as therapeutic agents for the treatment of dyslipidemia and potentially an array of other disease areas.     

Advances in treatment of pulmonary arterial hypertension: patent review

Introduction: Current therapeutic approaches for pulmonary arterial hypertension (PAH) commonly include use of prostacyclins, endothelin pathway antagonists or NO (nitric oxide) pathway modulators. These agents are non-specific and suffer from several important shortcomings including short half-lives, invasive routes of administration, higher dose and frequency requirements, and several dose-related systemic side effects. Hence, discovery of novel agents with improved therapeutic efficacy with respect to survival benefits and the development of non-invasive routes of administration are in critical need. Current research aimed at developing more selective therapies for PAH are focused both on agents acting on novel molecular targets, as well as, novel compounds acting on conventional pathways with improved characteristics.

Area covered: The present review covers recently filed (issued/application) patents (2010–2016) describing novel agents acting on investigational targets as well as novel compounds with improved characteristics acting on established targets. Patents describing combinations of conventional and investigational compounds are also discussed.

Expert opinion: PAH has recently been considered as cancer-like disease with over-proliferation of pulmonary arterial smooth muscle cells and endothelial cells. New cellular and molecular biological advances have revealed novel target/pathways involved in the pathogenesis and progression of PAH. Thus, discovery of agents that act on these novel pathways provides a promising avenue of research for improving therapeutic approaches for PAH.