Expert Opinion on Therapeutic Patents最新文献

Introduction: Pseudomonas aeruginosa (PA) is a Gram-negative bacterium that can cause a wide range of severe infections in immunocompromised patients. The most difficult challenge is due to its ability to rapidly develop multi drug-resistance. New strategies are urgently required to improve the outcome of patients with PA infections. The present patent review highlights the new molecules acting on different targets involved in the antibiotic resistance.

Area covered: This review offers an insight into new potential PA treatment disclosed in patent literature. From a broad search of documents claiming new PA inhibitors, we selected and summarized molecules that showed in vitro and in vivo activity against PA spp. in the period 2020 and 2023. We collected the search results basing on the targets explored.

Expert opinion: This review examined the main patented compounds published in the last three years, with regard to the structural novelty and the identification of innovative targets. The main areas of antibiotic resistance have been explored. The compounds are structurally unrelated to earlier antibiotics, characterized by a medium-high molecular weight and the presence of heterocycle rings. Peptides and antibodies have also been reported as potential alternatives to chemical treatment, hereby expanding the therapeutic possibilities in this field.

Introduction: Stimulator of Interferon Genes (STING) is an innate immune sensor. Activation of STING triggers a downstream response that results in the expression of proinflammatory cytokines (TNF-α, IL-1β) via nuclear factor kappa-B (NF-κB) or the expression of type I interferons (IFNs) via an interferon regulatory factor 3 (IRF3). IFNs can eventually result in promotion of the adaptive immune response including activation of tumor-specific CD8⁺ T cells to abolish the tumor. Consequently, activation of STING has been considered as a potential strategy for cancer treatment.

Areas covered: This article provides an overview on structures and pharmacological data of CDN-like and non-nucleotide STING agonists acting as anticancer agents (January 2021 to October 2023) from a medicinal chemistry perspective. The data in this review come from EPO, WIPO, RCSB PDB, CDDI.

Expert opinion: In recent years, several structurally diverse STING agonists have been identified. As an immune enhancer, they are used in the treatment of tumors, which has received extensive attention from scientific community and pharmaceutical companies. Despite the multiple challenges that have appeared, STING agonists may offer opportunities for immunotherapy.

Introduction: Breast cancer is the most frequently diagnosed cancer worldwide. With around 70% of breast cancers expressing the estrogen receptor (ER), molecules capable of antagonizing and degrading ER (SERDs) or covalently binding to and antagonizing ER (SERCAs) are at the forefront of efforts to bring better treatments to patients.

Areas covered: This review summarizes patent applications that claim estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs) identified using SciFinder between the period July 2021 to December 2023. A total of 91 new patent applications from 32 different applicants are evaluated with stratification into acidic SERDs, basic SERDs, SERCAs and miscellaneous degraders.

Expert opinion: The widespread adoption of fulvestrant in the treatment of ER+ breast cancer continues to stimulate research into orally bioavailable SERDs and SERCAs. A number of molecules have entered clinical development and, although some have been discontinued, a cohort of potential new treatments have generated encouraging efficacy and safety data. Notably, the first example of an oral SERD, elacestrant, has now been approved by the FDA and EMA, providing further encouragement for this class of targeted therapies.

Introduction: PIM Kinases (PIM-1, PIM-2, and PIM-3) have been reported to play crucial role in signaling cascades that govern cell survival, proliferation, and differentiation. Over-expression of these kinases leads to hematological malignancies such as diffuse large B cell lymphomas (DLBCL), multiple myeloma, leukemia, lymphoma and prostate cancer etc. PIM kinases as biomarkers and potential therapeutic targets have shown promise toward precision cancer therapy. The selective PIM-1, PIM-2, and/or PIM-3 isoform inhibitors have shown significant results in patients with advanced stages of cancer including relapsed/refractory cancer.

Areas covered: A comprehensive literature review of PIM Kinases (PIM-1, PIM-2, and PIM-3) in oncogenesis, the patented PIM kinase inhibitors (2016-Present), and their pharmacological and structural insights have been highlighted.

Expert opinion: Recently, PIM kinases viz. PIM-1, PIM-2, and PIM-3 (members of the serine/threonine protein kinase family) as therapeutic targets have attracted considerable interest in oncology especially in hematological malignancies. The patented PIM kinase inhibitors comprised of heterocyclic (fused)ring structure(s) like indole, pyridine, pyrazine, pyrazole, pyridazine, piperazine, thiazole, oxadiazole, quinoline, triazolo-pyridine, pyrazolo-pyridine, imidazo-pyridazine, oxadiazole-thione, pyrazolo-pyrimidine, triazolo-pyridazine, imidazo-pyridazine, pyrazolo-quinazoline and pyrazolo-pyridine etc. showed promising results in cancer chemotherapy.

Introduction: TRPA1 is a nonselective calcium channel, a member of the transient receptor potential (TRP) superfamily, also referred to as the 'irritant' receptor, being activated by pungent and noxious exogenous chemicals as well as by endogenous algogenic stimuli, to elicit pain, itching, and inflammatory conditions. For this reason, it is considered an attractive therapeutic target to treat a wide range of diseases including acute and chronic pain, itching, and inflammatory airway diseases.

Areas covered: The present review covers patents on TRPA1 antagonists disclosed from 2020 to present, falling in the following main classes: i) novel therapeutic applications for known or already disclosed antagonists, ii) identification and characterization of TRPA1 antagonists from natural sources, and iii) synthesis and evaluation of novel compounds.

Expert opinion: Despite the limited number of TRPA1 antagonists in clinical trials, there is an ever-growing interest on this receptor-channel as therapeutic target, mainly due to the relevant outcomes from basic research, which unveiled novel physio-pathological mechanisms where TRPA1 is believed to play a pivotal role, for example the Alzheimer's disease or ocular diseases, expanding the panel of potential therapeutic applications for TRPA1 modulators.

Introduction: SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) is a target of interest for cancer therapy due to its key role in the regulation of the RAS/MAPK signal transduction pathway downstream of Receptor Tyrosine Kinases (RTKs). Moreover, SHP2 can inhibit T cells via the PD-1/PD-L1 pathway. SHP2 plays a critical role in numerous physiological and pathological cellular processes, such as cell proliferation, survival, and migration.

Areas covered: This review examines SHP2 allosteric inhibitors reported in patents published in Espacenet and Scifinder databases from 2018 to present. An overview of claimed structures is conducted, focusing attention on structural modifications compared to SHP099, the first described allosteric inhibitor of SHP2.

Expert opinion: Multiple potent allosteric SHP2 inhibitors have been discovered, disclosed, and tested in a variety of preclinical cancer models with strong evidence of efficacy. Fifteen compounds are currently in clinical development, but none of them have been approved for marketing. Until now, long-term benefit of SHP2 inhibitors as monotherapy agents have not been demonstrated due to acquired mechanisms of resistance and/or lack of efficacy. However, combination therapies with a variety of agents, such as MEK, BRAF, EGFR, RAS-G12C and PDL-1 inhibitors, have high potential and are currently an extensive area of investigation.

Introduction: This review offers an updated perspective on the biomedical applications of prokaryotic carbonic anhydrases (CAs), emphasizing their potential as targets for drug development against antibiotic-resistant bacterial infections. A systematic review of literature from PubMed, Web of Science, and Google Scholar has been conducted to provide a comprehensive analysis.

Area covered: It delves into the pivotal roles of prokaryotic CAs in bacterial metabolism and their distinctions from mammalian CAs. The review explores the diversity of CA classes in bacteria, discusses selective inhibitors targeting bacterial CAs, and explores their potential applications in biomedical research. Furthermore, it analyzes clinical trials investigating the efficacy of carbonic anhydrase inhibitors (CAIs) and patented approaches for developing antibacterial CAIs, highlighting their translational potential in creating innovative antibacterial agents.

Expert opinion: Recent years have witnessed increased recognition of CA inhibition as a promising strategy against bacterial infections. Challenges persist in achieving selectivity over human isoforms and optimizing therapeutic efficacy. Structural biology techniques provide insights into unique active site architectures, guiding selective inhibitor design. The review underscores the importance of interdisciplinary collaborations, innovative drug delivery systems, and advanced drug discovery approaches in unlocking the full therapeutic potential of prokaryotic CA inhibitors. It emphasizes the significance of these efforts in addressing antibiotic resistance and improving patient outcomes.