Expert Opinion on Therapeutic Patents最新文献

Introduction: MALT1 paracaspase acts as a molecular scaffold and a proteolytic enzyme in immune cells. MALT1 has emerged as a promising drug target for cancer therapy, and especially for targeting MALT1 in aggressive lymphomas. Drug discovery programs have yielded potent and selective MALT1 protease inhibitors. First-in-class MALT1 inhibitors have been moved to early clinical trials to evaluate safety and efficacy.

Areas covered: This review will provide an update regarding the mode of action, the chemical space and therapeutic use of MALT1 inhibitors based on recent patents and the scientific literature (05/2021-12/2024).

Expert opinion: Allosteric inhibition is the preferred mode of action to inhibit the MALT1 protease. Chemical advances largely focus on improving binding and inhibition in the allosteric site of MALT1. New composition of matter has been generated, but a clinical proof for the safety and efficacy of allosteric MALT1 inhibitors is still pending. We still lack potent and selective competitive or covalent MALT1 inhibitors, indicating the challenges with targeting the active site. Further, MALT1 protein degraders and MALT1 scaffolding inhibitors have been developed, which may have distinct inhibitory profiles compared to allosteric MALT1 protease inhibitors, but more potent and selective compounds are needed to judge the feasibility and usefulness of these approaches.

Introduction: Since the approval of the first JAK inhibitor, ruxolitinib, in 2011, the development of JAK inhibitors has expanded significantly, with applications spanning autoimmune diseases, cancer, and inflammatory disorders. This review explores the challenges and therapeutic potential of JAK inhibitors and their evolution into proteolysis-targeting chimeras (PROTACs), which offer novel avenues for selective JAK modulation.

Areas covered: This review examines recent advancements in JAK inhibitors, including their mechanism of action, structure activity relationships, clinical applications, and emerging safety concerns. Additionally, PROTAC-based strategies targeting JAK proteins are discussed, highlighting their potential advantages over traditional small-molecule inhibitors. A comprehensive patent literature search was conducted, focusing on publications and patents from 2022 to 2023. Key selection criteria included small-molecule JAK inhibitors and JAK-targeting PROTACs with associated preclinical data.

Expert opinion: While JAK inhibitors have transformed the treatment of various diseases, safety concerns, including risks of venous thromboembolism and herpes zoster, pose challenges to their widespread use. The advent of JAK-targeting PROTACs represents a promising strategy to enhance selectivity and mitigate off-target effects. However, further research is needed to optimize their therapeutic potential and establish their clinical viability.

Introduction: EZH2 forms the PRC2 complex with SUZ12 and EED. As a crucial catalytic subunit of PRC2, EZH2 modifies histone H3K27 via its SET domain, resulting in chromatin condensation and suppressing the transcription of related target genes. EZH2 not only functions in PRC2-dependent transcriptional repression but can also activate gene expression in PRC2-independent circumstances or regulate the activity of downstream genes via its own activating mutations. On the basis of the critical role of EZH2 in cancer, the development of inhibitors targeting EZH2 provides a new strategy for cancer therapy.

Areas covered: The purpose of this review is to summarize the molecular mechanisms of EZH2 inhibitors and emphasize the research progress on EZH2 inhibitors published in the patent literature in recent years. The literature and patent databases of PubMed, Web of Science, SCIFinder, WIPO, USPTO, EPO, and CNIPA were combined to search for more effective EZH2 inhibitors.

Expert opinion: Recently, a wide range of structurally diverse EZH2 inhibitors, particularly EZH2 degraders, have been identified. These EZH2 modulators have demonstrated significant potential in treating various diseases, with cancer being a primary focus. The development of small molecules targeting EZH2 with distinct pharmacological effects is poised with numerous opportunities.

Introduction: Nuclear receptor retinoid-related orphan receptor gamma-t (RORγt) is a major transcription factor for Th17 cell differentiation and IL-17 production. RORγt has been considered as a promising drug target for the treatment of IL-17-mediated inflammatory diseases. Numerous small molecule inhibitors have been discovered, and more than 20 of RORγt inhibitors have been advanced to clinical trials. However, none of these compounds has yet achieved market approval.

Areas covered: This manuscript summarizes the development of 22 clinical-stage RORγt inhibitors, including their structures, patent applications, and clinical trial status, based on publications and patents available up to November 2024.

Expert opinion: The discovery of RORγt inhibitors was considered as an exciting field for the development of small molecular treatments, which has gone through a boom period in the past 10 years. However, some of the leading RORγt inhibitors recently failed in clinical trials due to lack of efficacy or having some safety concerns, although a few small molecule candidates targeting RORγt are still in trials and more in preclinical studies. Realizing the challenge, researchers started to develop different approaches such as dual targeting or exploring new indications, utilizing the potential value of RORγt inhibitors.

Introduction: Atypical chemokine receptor 3 (ACKR3) (formerly CXCR7) regulates various biological processes through its ligands and is closely associated with numerous diseases, including inflammation, cancer, cardiovascular diseases (CVDs), pain, and neurological disorders. Therefore, ACKR3 has emerged as a potential target for disease treatment.

Areas covered: This review summarizes the ACKR3 modulators published in patents from 2019 to 2024 using data from Google Patents, the European Patent Office, and the World Intellectual Property Organization's online databases. This includes information on their chemical structures, syntheses, activities, and developmental stages.

Expert opinion: ACKR3 agonists gained traction as a treatment for cardiovascular and pain conditions. WW-12, which was derived from the chemical modifications of conolidine, became a novel small-molecule pain modulator by activating ACKR3, which in turn boosted endogenous opioid peptides for the classical opioid receptors.ACKR3 antagonist ACT-1004-1239 from Idorsia Pharmaceuticals Ltd. has demonstrated the ability to treat cancer, acute lung injury/ARDS, and autoimmune diseases, including multiple sclerosis. The outcomes of these clinical trials will direct the development and indications of future ACKR3 modulators.

Introduction: PAD4 mediates the post-translational modification of arginine residues into citrulline which can have profound effects on protein structure, function and interactions. Protein citrullination and neutrophil extracellular trap (NET) formation associated with increased PAD4 activity have been implicated in the development of autoimmune conditions, cardiovascular diseases, neurodegenerative disorders, and cancer. PAD4 inhibitors have been shown to suppress citrullination and NETs formation.

Areas covered: This review covers 10 years of industrial drug discovery campaigns reported in 28 patent applications from 10 companies. Cortellis, the World Intellectual Property Organization website, Scopus and SciFinder were used to search the patent literature using the keywords 'PAD4' and 'PAD4 inhibitor.' Most of the reported inhibitors share the same core scaffold with varied decoration of different complexity, including highly functionalized macrocycles, with some in vivo and pharmacokinetic (PK) data reported for selected examples.

Expert opinion: Despite PAD4's clear involvement in multiple disease pathways, its detailed mechanism remains insufficiently understood. Selective and potent compounds with improved PK properties have been provided but most research on PAD4 is still at the experimental stage or preclinical development; the most promising is JBI-1044, at the IND stage, while some companies have turned to antibodies despite considerable previous investment in small molecules.

Introduction: The fat mass and obesity-associated protein (FTO) catalytically demethylates RNA N⁶-methyl adenosine (m⁶A) modification, dynamically regulates gene expression in eukaryotes. Interestingly, FTO is highly expressed and functions as an oncogenic factor in a wide range of cancers. Therefore, using small-molecule inhibitors to target FTO has been established as a promising therapeutic strategy for combating cancers.

Areas covered: Patent literature claiming novel chemical entities as FTO inhibitors disclosed from 2017 to present is available in Espacenet, including dozens of patent documents.

Expert opinion: The pivotal influence of FTO demethylase in a particular epigenetic layer of regulation of gene expression renders it promising for FTO to be a therapeutical target for many diseases, including malignant cancers. Several institutions were prompted and have patented chemical frameworks as FTO inhibitors. Remarkedly, the FTO inhibitor CS1 (Bisantrene) has advanced to clinical trials for treating acute myeloid leukemia (AML). The successful advancement of CS1 into clinical trials would continuingly stimulate researches on RNA epigenetic enzymes targeted first-in-class anticancer drug discovery.

Introduction: Small molecule kinase inhibitors are crucial in the treatment of tumors, and the development of novel inhibitors is a primary approach to combat the continuous emergence of drug resistance. Macrocyclization has emerged as a cutting-edge strategy to enhance the potency, selectivity, and pharmacokinetic properties of these inhibitors by altering their biological and physicochemical characteristics compared to their acyclic counterparts.

Areas covered: The present article provides a comprehensive overview of the recent advancements in macrocyclic small molecule inhibitors and their inhibitory activities against various cancer cells, which have been patented since 2019.

Expert opinion: To date, small-molecule kinase inhibitors have demonstrated remarkable therapeutic efficacy in clinical settings. Recent patents have primarily focused on addressing challenges associated with resistance mutations. Despite the significant success achieved in developing selective kinase agents, the identification of new targets and emergence of novel mutations necessitate the development of novel small-molecule inhibitors. Macrocyclic compounds possess distinctive conformational constraints, enhanced inhibitor potency and selectivity, as well as favorable pharmacokinetic properties, rendering them safe, efficient, selective, low-toxicity agents with unique structural characteristic.

Introduction: P2Y₁₂ receptor (P2Y₁₂R) is a G protein-coupled receptor that plays a crucial role in regulating platelet activation and aggregation. P2Y₁₂R is involved in various processes such as renal fibrosis, cancer, ischemic disease, and related complications, making it an appealing target for therapeutic interventions. Over the past decade, the discovery and development of P2Y₁₂R antagonists have significantly advanced, offering novel treatment options that improve clinical outcomes.

Areas covered: This review covers P2Y₁₂R antagonists reported in patents issued in the online databases of the World Intellectual Property Organization and the European Patent Office from 2019 to 2024. This review introduces the development of existing antagonists and evaluates the therapeutic potential of these compounds.

Expert opinion: Reversible P2Y₁₂R antagonists offer a potentially safer alternative to the currently dominant irreversible antagonists on the market, as they allow for more controlled platelet inhibition and can reduce the toxicity and adverse effects associated with conventional drugs. Importantly, the integration of computational drug design and molecular docking studies in the discovery and optimization of P2Y₁₂R antagonists represents a significant advancement in precision medicine. This not only provides valuable structural scaffolds but also stimulates novel ideas for developing promising drugs that are both safe and efficacious.

Introduction: TRPV1, a pivotal therapeutic target for chronic pain and pruritus, has been validated in the pathogenesis of several pathologies from diabetes to cancer. Despite the constellation of chemical structures and strategies, none of these molecules has yet been clinically developed as a new drug application due to safety concerns, particularly in thermoregulation. Thus, clinical development of TRPV1 modulators remains a challenge.

Areas covered: This review covers the patent literature on TRPV1 modulators (2019-2024, PubMed, Google Patents, and Espacenet), from orthosteric ligands to innovative compounds of biotechnological origin such as interfering RNAs or antibodies, and dual modulators that can act on TRPV1 and associated proteins in different tissues.

Expert opinion: Therapeutic strategies that preferentially act on dysfunctional TRPV1 channels appear essential, along with a superior understanding of the underlying mechanisms affecting changes in core body temperature (CBT). Recent findings describing differential receptor interactions of antagonists that do not affect CBT may pave the way to the next generation of orally active TRPV1 inhibitors. Although we have thus far experienced a bitter feeling in TRPV1 drug development, the recent progress in different disciplines, including human-based preclinical models, will set an interdisciplinary approach to design and develop clinically relevant TRPV1 modulators.