Expert Opinion on Therapeutic Patents最新文献

Introduction: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed.

Area covered: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023.

Expert opinion: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.

Introduction: HMGB1 is a non-histone chromatin protein released or secreted in response to tissue damage or infection. Extracellular HMGB1, as a crucial immunomodulatory factor, binds with several different receptors to innate inflammatory responses that aggravate acute and chronic liver diseases. The increased levels of HMGB1 have been reported in various liver diseases, highlighting that it represents a potential biomarker and druggable target for therapeutic development.

Areas covered: This review summarizes the current knowledge on the structure, function, and interacting receptors of HMGB1 and its significance in multiple liver diseases. The latest patented and preclinical studies of HMGB1 inhibitors (antibodies, peptides, and small molecules) for liver diseases are summarized by using the keywords 'HMGB1,' 'HMGB1 antagonist, HMGB1-inhibitor,' 'liver disease' in Web of Science, Google Scholar, Google Patents, and PubMed databases in the year from 2017 to 2023.

Expert opinions: In recent years, extensive research on HMGB1-dependent inflammatory signaling has discovered potent inhibitors of HMGB1 to reduce the severity of liver injury. Despite significant progress in the development of HMGB1 antagonists, few of them are approved for clinical treatment of liver-related diseases. Developing safe and effective specific inhibitors for different HMGB1 isoforms and their interaction with receptors is the focus of future research.

Introduction: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions.

Area covered: This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation.

Expert opinion: To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.

Introduction: The search for novel compounds targeting Peroxisome Proliferator-Activated Receptors (PPARs) is currently ongoing, starting from the previous successfully identification of selective, dual or pan agonists. In last years, researchers' efforts are mainly paid to the discovery of PPARγ and δ modulators, both agonists and antagonists, selective or with a dual-multitarget profile. Some of these compounds are currently under clinical trials for the treatment of primary biliary cirrhosis, nonalcoholic fatty liver disease, hepatic, and renal diseases.

Areas covered: A critical analysis of patents deposited in the range 2020-2023 was carried out. The novel compounds discovered were classified as selective PPAR modulators, dual and multitarget PPAR agonists. The use of PPAR ligands in combination with other drugs was also discussed, together with novel therapeutic indications proposed for them.

Expert opinion: From the analysis of the patent literature, the current emerging landscape sees the necessity to obtain PPAR multitarget compounds, with a balanced potency on three subtypes and the ability to modulate different targets. This multitarget action holds great promise as a novel approach to complex disorders, as metabolic, inflammatory diseases, and cancer. The utility of PPAR ligands in the immunotherapy field also opens an innovative scenario, that could deserve further applications.

Introduction: The 90-kDa heat shock protein (HSP90) functions as a molecular chaperone, it assumes a significant role in diseases such as cancer, inflammation, neurodegeneration, and infection. Therefore, the research and development of HSP90 inhibitors have garnered considerable attention.

Areas covered: The primary references source for this review is patents obtained from SciFinder, encompassing patents on HSP90 inhibitors from the period of 2020 to 2023.This review includes a thorough analysis of their structural attributes, pharmacological properties, and potential clinical utilities.

Expert opinion: In the past few years, HSP90 inhibitors targeting ATP binding pocket are still predominate and one of them has been launched, besides, novel drug design strategies like C-terminal targeting, isoform selective inhibiting and bifunctional molecules are booming, aiming to improve the efficacy and safety. With expanded drug types and applications, HSP90 inhibitors may gradually becoming a sagacious option for treating various diseases.

Introduction: Cysteine proteases are involved in a broad range of biological functions, ranging from extracellular matrix turnover to immunity. Playing an important role in the onset and progression of several diseases, including cancer, immune-related and neurodegenerative disease, viral and parasitic infections, cysteine proteases represent an attractive drug target for the development of therapeutic tools.

Areas covered: Recent scientific and patent literature focusing on the design and study of cysteine protease inhibitors with potential therapeutic application has been reviewed.

Expert opinion: The discovery of a number of effective structurally diverse cysteine protease inhibitors opened up new challenges and opportunities for the development of therapeutic tools. Mechanistic studies and the availability of X-ray crystal structures of some proteases, alone and in complex with inhibitors, provide crucial information for the rational design and development of efficient and selective cysteine protease inhibitors as preclinical candidates for the treatment of different diseases.

Introduction: Schiff bases are compounds with characteristic features of azomethine linkage (-C=N-). Schiff bases are capable of coordinating with metal ions via azomethine nitrogen. Schiff base derivatives and their metal complexes are known for intriguing novel therapeutic properties. In organic synthesis, the Schiff base reaction is prime in creating the C-N bond. Synthetic accessibility and structural diversity are the salient features for facile synthesis of Schiff base hybrids via a condensation reaction between an aldehyde/ketone and primary amines.

Area covered: This review aims to provide a comprehensive overview of the commendable medicinal applications of Schiff base derivatives and their metal complexes patented from 2016 to 2023.

Expert opinion: Schiff base derivatives are exceptional molecules for their assorted applications in medicinal chemistry. Several Schiff base products are marketed as drugs, and plenty of room is available for the purposive synthesis of new compounds in a diverse pool of disciplines. Expansion in the derivatization of Schiff bases in innumerable directions with multitudinous applications makes them 'magical molecules.' These compounds have proved extraordinary, from medicinal chemistry to other fields outside medicine. This review covers the therapeutic importance of Schiff base derivatives and aims to cover the patents published in recent years (2016-2023).

Introduction: Tropane-derived medications have historically played a substantial role in pharmacotherapy. Both natural and synthetic derivatives of tropane find application in addressing diverse medical conditions. Prominent examples of tropane-based drugs include hyoscine butylbromide, recognized for its antispasmodic properties, atropine, employed as a mydriatic, maraviroc, known for its antiviral effects. trospium chloride, utilized as a spasmolytic for overactive bladder, and ipratropium, a bronchodilator.

Areas covered: We compiled patents pertaining to the biological activity of substances containing tropane up to the year 2023 and categorized them according to the specific type of biological activity they exhibit. ScienceFinder, ScienceDirect, and Patent Guru were used to search for scientific articles and patent literature up to 2023.

Expert opinion: Pharmaceutical researchers in academic and industrial settings have shown considerable interest in tropane derivatives. Despite this, there remains a substantial amount of work to be undertaken. A focused approach is warranted for the exploration and advancement of both natural and synthetic bioactive molecules containing tropane, facilitated through collaborative efforts between academia and industry. Leveraging contemporary techniques and technologies in medicinal and synthetic chemistry, including high throughput screening, drug repurposing,and biotechnological engineering, holds the potential to unveil novel possibilities and accelerate the drug discovery process for innovative tropane-based pharmaceuticals.

Introduction: Thymosins are small proteins found mainly in the thymus. They are involved in several biological processes, including immunoregulation, angiogenesis, and anti-inflammatory activity. Due to these multiple activities, thymosins are widely used as therapeutics. In fact, these peptides have shown interesting results in the treatment of eye disorders, anticancer therapy, and dysregulated immune disorders.

Area covered: We analyzed the thymosins therapeutic patent landscape describing the most significant patents published after 2018 and originally written in English, classified according to the different type of functions and diseases. We searched 'Thymosin' on Patentscope and Espacenet.

Expert opinion: Thymalfasin (Zadaxin) is the only FDA-approved thymosine-based drug used to treat chronic hepatitis B and C and as a chemotherapy inducer. This outcome demonstrates how thymosins can be exploited as therapeutics, especially in immunological and anti-cancer therapies. However, the development of modified thymosins could expand their therapeutic interest and application in different diseases. In fact, by chemical modifications, it is possible to increase proteolytic stability in the biological environment, enhance cell permeability, and stabilize the secondary structure of the peptide. Finally, the development of shorter sequences could reduce the cost and production time of these thymosin-based drugs.