Expert Opinion on Therapeutic Patents最新文献

Introduction: Tumor cell heterogeneity poses a challenge to monotherapy, as a single drug cannot kill all heterogeneous cancer cells of a tumor. The surviving cells may develop resistance, potentially leading to tumor recurrence. The combination therapy targets the disease through multiple mechanisms. Combinations of histone deacetylase (HDAC) inhibitor(s) with other inhibitor(s) have represented promising cancer chemotherapeutics by altering the epigenetic landscape of cancer cells by restoring acetylation and reactivating tumor suppressor genes, leading to cell cycle arrest, promoting apoptosis, and thus inhibiting cancer cell proliferation.

Areas covered: The patent literature (2020-present) on rational combinations of HDAC inhibitor(s) for cancer chemotherapy has been searched and reviewed from Google Patents, Patentscope, Espacenet, WIPO, and USPTO to provide an expert opinion on rational combinations for improved, optimized, and precise cancer therapy. This first part of a two-part review highlights the patent granted for the combination.

Expert opinion: The combination of HDAC inhibitors with other inhibitors, including Janus kinase (JAK), aurora kinase, tubulin, Sirtuin 2, and/or topoisomerase inhibitors, demonstrated a synergistic anti-cancer effect. Dual and multi-target inhibitors showed enhanced therapeutic efficacy in relapsed and refractory cases characterized by epigenetic dysregulation via histone modifications and alterations that contribute to disease progression.

Introduction: Type 2 diabetes mellitus (T2DM) affects over 530 million individuals globally, and is projected to reach 783 million by 2045, necessitating novel therapeutic strategies beyond current options. G-protein-coupled receptor 120 (GPR120), a lipid sensor regulating insulin sensitivity and inflammation, has gained attention as a promising target.

Areas covered: This review evaluates 25 patents and peer-reviewed studies (2020-2025) on GPR120 agonists. It highlights potent thiophene derivatives (EC₅₀ < 50 nM), sulfonamides, and stable fatty acid mimetics. Special attention is given to β-arrestin-biased agonists that improve glucose control (25% AUC reduction), improve insulin sensitivity (30% glucose drop), and reduce inflammation (40% TNFα inhibition). These compounds enhance GLP-1 secretion (a 2-fold increase), offering triple therapeutic benefits for diabetes. Sources were identified through a structured search of recent scientific literature and databases.

Expert opinion: GPR120 agonists, particularly β-arrestin-biased ligands, hold significant potential for T2DM treatment by modulating glucose homeostasis and inflammation. However, challenges like receptor desensitization and translational barriers such as species-specific receptor expression, off-target activity, and suboptimal pharmacokinetics must be addressed. Future research should optimize drug design to enhance efficacy and safety, paving the way for novel metabolic disorder therapies.

Introduction: Checkpoint kinase 1 (CHK1), a serine/threonine kinase, plays an important role in the DNA damage response (DDR), such as cell cycle checkpoints, DNA repair, transcriptional regulation, and apoptosis inhibition. CHK1 has emerged as a promising therapeutic target for cancer treatment. To date, over 15 CHK1 inhibitors have advanced into clinical trials, yet none have been approved for marketing.

Areas covered: A comprehensive patent review of literature from January 2019 to December 2024 on CHK1 inhibitors in oncology, their combination products, and structural insights have been reviewed through searching relevant information in Scopus, Espacenet, Web of Science, World Intellectual Property Organization, Google Patent databases, Cortellis Drug Discovery Intelligence, and United States Patent and Trademark Office.

Expert opinion: Considering the current advancements and the state of the field, the development of potent and selective CHK1 inhibitors with novel skeleton, either as monotherapies or in combination therapies, is of paramount importance. Ongoing research focuses on rational drug design, synergistic treatment integration, and predictive biomarkers identification. These advancements, along with future progress in the realm of CHK1 inhibitors, offer great promise as a pivotal strategy in biomarker-guided cancer therapeutics.

Introduction: Glycogen synthase kinase-3β (GSK-3β) is a proline-directed serine/threonine kinase identified over 40 years ago. It is the key enzyme involved in glycogen biosynthesis and is expressed in all human tissues. Overexpression of GSK-3β is linked to several diseases, including diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease, and cancer. Owing to its critical role in the pathophysiology of these diseases, GSK-3β has emerged as a validated and potential target for therapeutic intervention. In recent years, significant progress has been made in developing novel GSK-3 inhibitors. Some of these new inhibitors have shown promising results in treating some of these diseases.

Areas covered: This review covers patent literature on various GSK-3β inhibitors published between 2019 and 2024. This review also discusses the recent clinical developmental status of some of the promising GSK-3 inhibitors.

Expert opinion: Although many heterocyclic compounds from natural as well as synthetic origin have shown promising inhibitory effects against GSK-3β, most of them have not yet progressed to the development stage. However, a critical review of their structures and biological profiles reveals significant potential for further development.

Introduction: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, with epidermal growth factor receptor (EGFR) mutations being the primary driver of tumor progression. This review highlights the significance of fourth-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) in addressing acquired resistance mechanisms, such as the C797S mutation, which compromises the efficacy of third-generation inhibitors like Osimertinib and explores their potential to revolutionize NSCLC treatment through enhanced molecular specificity.

Areas covered: This review covers the latest progress in patented fourth-generation EGFR-TKIs and their clinical trial status for the treatment of NSCLC from 2017 to the present.

Expert opinion: Osimertinib, a third-generation EGFR inhibitor, revolutionized treatment for T790M mutations but is limited by resistance from C797S mutations. Fourth-generation EGFR inhibitors, incorporating scaffolds like aminopyrimidine and quinazoline, are designed to selectively target resistant EGFR variants, including L858R/T790M/C797S. Preclinical trials highlight the potential of sulfonyl and phosphine oxide-based compounds for their potency, selectivity, and favorable pharmacokinetics. Promising clinical trials with inhibitors like BDTX-1535, JIN-A02, and HS-10504 could redefine NSCLC treatment, with future success likely relying on innovative strategies, such as combination therapies, to combat resistance and enhance efficacy.

Introduction: The rise of tissue-agnostic therapies has revolutionized cancer treatment, with therapies targeting NTRK fusions leading the way. TRK inhibitors like larotrectinib and entrectinib marked a paradigm shift - prioritizing molecular alterations over the tumor's anatomical location. Acquired resistance remains a significant challenge, with next-generation inhibitors and combination strategies at the forefront of efforts to enhance the clinical efficacy of TRK-targeted therapies.

Areas covered: This review discusses patents published in 2023 and 2024 covering inhibitors of the TRK family, extending our ongoing review series on TRK inhibitors. Patent searches were conducted using the key word 'TRK*' and 'inhibitor' in Google Patents database to identify novel TRK-targeting inhibitors and therapeutic strategies.

Expert opinion: Ongoing advancements in TRK inhibitor development, combination therapies, and precision diagnostics continue to elevate the potential of treatment outcomes. Recent patent filings reflect the expanding promise of TRK inhibitors for NTRK fusion-driven cancers. However, widespread adoption of high-throughput screening remains crucial unlocking their full therapeutic value and delivering truly precision-guided care. Combination therapies with TRK inhibitors are emerging as a key strategy to enhance efficacy and overcome resistance. The FDA's recent approval of repotrectinib underscores progress in the TRK inhibitor landscape, while highlighting the continued need for innovation.

Introduction: Rearranged during transfection (RET) is a receptor tyrosine kinase essential for cell signaling processes such as proliferation, differentiation, and migration. RET alterations, including point mutations and gene fusions, contribute to oncogenesis. Recent advances in precision oncology have led to the development of selective RET inhibitors with improved safety and efficacy profiles.

Areas covered: This review discusses recent innovations in RET inhibitor development, with a focus on small-molecule patents published from 2022 to 2024. A comprehensive literature search was conducted using SciFinder and PatentScope with the keywords 'RET' and 'RET inhibitor.' The review summarizes the structural classes, target profiles, and potential advantages of newly patented compounds, particularly those designed to overcome known resistance mechanisms.

Expert opinion: While selective RET inhibitors such as selpercatinib have shown clinical success and expanded indications, their use is limited by adverse events and emerging resistance mechanisms. Next-generation RET inhibitors that address these limitations represent a critical frontier in drug development.

Introduction: Formyl peptide receptors (FPRs) belong to the family of class A G-protein-coupled receptors that are important for immune modulation and inflammation and are emerging as potential therapeutic targets for several inflammatory diseases. FPRs have shown therapeutic roles in the management of cardiovascular diseases, neuroinflammation, and cancer. Biased agonists are an active topic in the further revisions that encompass the utilization of a definite subset of signaling pathways to improve therapeutic maladies, in parallel with reducing the negative effects.

Areas covered: This review surveys the modulators of FPR1 and FPR2 that have been published in patents from 2021 to 2024, to summarize the categorization of agonists and antagonists and discuss their possible clinical uses. A targeted patent search was performed using the Taiwan Patent GO Showcases database (https://tiponet.tipo.gov.tw/gpss/).

Expert opinion: We examine newly disclosed patents concerning FPR modulators, with all specified compounds classified as either FPR1 or FPR2 modulators. Receptor cross-reactivity, ligand promiscuity, and receptor variations across species are challenges encountered during drug formulation. Further research into different types of biased agonists and the synthesis of potent and selective ligands is essential to overcome these obstacles and facilitate the eventual therapeutic use of biased signaling in inflammation and diseases.

Introduction: Rho-associated protein kinases (ROCK) play a crucial role in various biological processes, making them a valuable therapeutic target. Recent FDA approvals of ROCK-targeting drugs have brought renewed focus to this area, which this review aims to explore.

Areas covered: This review examines patents published from 2017 to 2023, highlighting novel ROCK inhibitors, progress on previously studied compounds, and new therapeutic applications. A thorough literature search was conducted using patent databases and relevant publications.

Expert opinion: Fasudil, ripasudil, netarsudil, and belumosudil are the primary ROCK inhibitors approved for human use. Despite some pharmacokinetic challenges, research in this field continues to advance, with significant potential for further clinical development.

Introduction: The emergence of drug resistance poses a serious threat to cancer chemotherapy by a single agent. Tumor cell heterogeneity, mutation, and/or desensitization of receptor render monotherapy ineffective. Combination encompassing multiple targets or biochemical pathways seems promising for cancer treatment. Combination of HDAC inhibitor(s) with other inhibitor(s) has shown synergistic activity in cancer chemotherapy by modulating a variety of therapeutic targets including epigenetic target of cancer cells by restoring acetylation and reactivating tumor suppressor genes leading to cell cycle arrest, promoting apoptosis, and thus inhibiting cancer cell proliferation.

Areas covered: A comprehensive published patent literature (2020-present) on rational combinations of HDAC inhibitor(s) for cancer chemotherapy has been retrieved and reviewed from various patent databases including Google Patents, Espacenet, Patentscope, WIPO, and USPTO to analyze the rational combinations for better, optimized, and precise cancer therapy. In this second part of two-part review, we highlighted the patent published for the combination.

Expert opinion: The HDAC inhibitor(s) in combination with other therapeutically relevant inhibitor(s) such as MAPK, GSK3, PI3K/mTOR, PARP, CDK9, HSP90, BTK, BRD4, JAK, VEGF, ALK, PD-1, or PDE inhibitor showed synergistic anti-cancer activity. These combinations not only overcame drug resistance but also acted against relapsed/refractory cancers.