Expert Opinion on Therapeutic Patents最新文献

Introduction: The hepatitis B virus (HBV) core protein is a significant therapeutic target due to its essential role in HBV replication. Over the past five years, numerous structurally unique CpAMs have been patented. However, no compounds have been approved due to various issues such as poor pharmacokinetics (PK) and hepatotoxicity. As a result, there is an urgent need to develop novel CpAMs without these limitations.

Areas covered: This review provides a comprehensive analysis of patents related to CpAMs from 2019 to the present, with the aim of delineating the chemical evolution that has occurred in the pursuit of more promising CpAMs. The sources of patent information included databases of the European Patent Office, the China Patent Office and the U.S.A. Patent Office, while relevant research articles were accessed through PubMed.

Expert opinion: During the optimization of CpAMs, striking a good balance between activity and druggability usually poses a certain challenge while the emergence of drug resistance issues further complicates the development process. A comprehensive analysis of the structural features of CpAMs and identification of essential patterns in chemical evolution can reveal common principles that improve pharmacodynamic (PD) and PK profiles, thereby facilitating the discovery of next-generation CpAMs.

Introduction: Lysine-specific demethylase 1 (LSD1) and histone deacetylase 6 (HDAC6) are key epigenetic regulators involved in histone demethylation and deacetylation processes that impact chromatin structure and gene expression. JBI-802 marks a major advancement as the first novel, orally available LSD1/HDAC6 dual inhibitor currently in clinical trials.

Areas covered: This review provides a comprehensive overview of the discovery and development of JBI-802, detailing its structure-activity relationship (SARs), chemical synthesis, biological activity, and clinical progress. Other dual LSD1/HDAC6 inhibitors and the challenges are briefly discussed, underscoring the therapeutic potential of dual inhibition in disease treatment. The literature search is performed using SciFinder, Google patent, ClinicalTrials databases, and PubMed.

Expert opinion: The dual LSD1/HDAC6 inhibitor JBI-802 demonstrates robust anti-proliferative activity, significant antitumor effects in multiple hematologic malignancies, and superior efficacy in combination with checkpoint inhibitors in the CT-26 syngeneic mouse model. JBI-802 is currently undergoing phase I/II clinical trials in patients with advanced solid tumors, myeloproliferative neoplasms (MPN), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with thrombocytosis. However, the potential on-target toxicity, off-target interactions and selectivity concerns deservee more attention.

Introduction: Hematopoietic progenitor cell kinase (HPK1) is a serine/threonine kinase of MAP4K family. It negatively regulates T cell receptor and B cell signal transduction. The loss of HPK1 kinase function increases the secretion of cytokines and enhances T cell signal transduction, virus clearance and tumor growth inhibition. Therefore, HPK1 is considered as a promising drug target for tumor immunotherapy.

Area covered: This article surveys the patents published since 2021 aiming to analyze the structural features of scaffolds and the patent landscape. It also discusses the recent clinical developments and provides perspectives on the challenges and the future directions.

Expert opinion: HPK1 kinase is a viable drug target, and there is an increasing number of clinical studies on HPK1 inhibitors. In the clinical research of HPK1 inhibitors, there are mainly two ways: monotherapy and combination therapy. In recent years, HPK1 degraders derived from PROTAC technology have shown promises along with HPK1 inhibitors. It is hopeful that small molecule inhibitors or degraders targeting HPK1 will gain FDA approval for treatment of human diseases in the near future.

Databases searched and inclusive dates: A rapid survey of literature reports using keyword 'HPK1' in SciFinder® search engine yielded about 180 papers since 2021.

Introduction: Targeting immune checkpoint proteins (ICPs) via small molecules open a new window for cancer immunotherapy. Herein, we summarize recent advances of small molecules with novel chemical structures targeting ICPs, discusses their anti-tumor efficacies, which are important for the development of novel small molecules for cancer immunotherapy.

Areas covered: In this review, the latest patents and literature were gathered through the comprehensive searches in the databases of European Patent Office (EPO), Cortellis Drug Discovery Intelligence (CDDI), PubMed and Web of Science using ICPs and compounds as key words.

Expert opinion: To develop novel weapons to fight against cancer, small molecules targeting ICPs including CTLA-4, LAG-3, PD-L1, Siglec-9, TIM-3, TIGIT, and VISTA have been synthesized and evaluated in succession. Chief among them are the small molecules targeting PD-L1, which have been intensively investigated in recent years. Various in vitro assays such as ALPHA, HTRF binding assay, NFAT assay have been successfully developed to screen novel IPCs inhibitors. However, the in vivo assay, for example, using double-humanized PD-1/PD-L1 (hPD-1/hPD-L1) mouse as evaluation model, are seldom reported. Novel pharmacophores with new working mechanisms such as proteolysis targeting chimeras (PROTACs) and peptides are needed to enhance the therapeutic efficacy.

Introduction: Bromodomain-containing protein 4 (BRD4) stands as a pivotal member within the Bromodomain and Extra-Terminal Domain (BET) family, contributing significantly to epigenetic control and gene expression. Given its association with various cancers, BRD4 emerges as a promising therapeutic target, suggesting a substantial role in the treatment of diverse pathological conditions.

Areas covered: The present review is centered on patent applications concerning inhibitors targeting BRD4's bromodomain site, published from 2020 to present. A comprehensive evaluation was conducted on a total of 70 applications. The latest patented studies of BRD4 are summarized by using the keywords 'BRD4' in SciFinder, PubMed, and The lens Patents and databases in the year from 2020 to present.

Expert opinion: Despite the substantial progress achieved in the clinical research of numerous BET bromodomain inhibitors, their development remains fraught with challenges. To mitigate the dose-limiting toxicity (DLT) and other clinical adverse effects associated with pan-BET inhibitors, current research efforts are increasingly focus on the development of selective BRD4-BD1 or -BD2 inhibitors. These selective inhibitors exhibit considerable potential as more efficacious candidate drugs, thereby paving the way for novel avenues in both fundamental and translational research within this domain.

Introduction: Kelch-like ECH-associated protein 1 (Keap1), an E3 ligase negatively regulating the nuclear factor erythroid 2-related factor 2 (Nrf2), has emerged as an auspicious drug target for treating ailments associated with oxidative stress and inflammation. Discovery of Keap1 inhibitors have attracted significant interest.

Areas covered: This review covers patents on Keap1 inhibitors from 2019 to 2024, providing a comprehensive analysis of their structural characteristics, optimization strategies, pharmacological properties and clinical progress.

Expert opinion: Extensive efforts have been devoted to enhance potency and drug-like properties of Keap1 inhibitors. Strategies such as ROS-cleavable prodrug design, bivalent inhibition and PROTACs are emerging. As the range of drug types and applications expands, Keap1 inhibitors are becoming a sagacious option for disease treating.

Introduction: The chemokine receptor CXCR4 has been under intense study due to the central role it plays in immune system regulation and the pathology of human disease. Although the first CXCR4 drug plerixafor emerged over a decade ago (2007), recently the first peptide (motixafortide, 2023) and the first oral small molecule (mavorixafor, 2024) CXCR4 antagonists became FDA approved.

Areas covered: This article describes patent documents published during the period of 2019 through 2024 for both small molecule and peptides. This IP includes few new chemotypes, with most being extensions of existing structural classes. There is also less significant IP covering peptide-based therapeutics than those covering small molecules. Notably, multiple therapeutic uses have also emerged. Patents were searched from SciFinder (CAS) and Google Patents with the term CXCR4 antagonists. Patents were selected according to whether they fit into the classification of small molecules or peptides.

Expert opinion: In the last 5 years there has been significant advancement in CXCR4 antagonists as gauged by the FDA approval of two drugs. The search for second and third generation compounds will be the focus of future efforts with new uses and better properties which likely could come from some of the IP described herein.

The identification of disease-specific subtypes can provide valuable insights into disease progression and potential individualized therapies, important aspects of precision medicine given the complex nature of disease heterogeneity. The advent of high-throughput technologies has enabled the generation and analysis of various molecular data types, such as single-cell RNA-seq, proteomic, and imaging datasets, on a large scale. While these datasets offer opportunities for subtype discovery, they also pose challenges in finding subtype signatures due to their high dimensionality. Feature selection, a key step in the machine learning pipeline, involves selecting signatures that reduce feature size for more efficient downstream computational analysis. Although many existing methods focus on selecting features that differentiate known diseases or cell states, they often struggle to identify features that both preserve heterogeneity and reveal subtypes. To address this, we utilized deep metric learning-based feature embedding to explore the statistical properties of features crucial for preserving heterogeneity. Our analysis indicated that features with a notable difference in interquartile range (IQR) between classes hold important subtype information. Guided by this insight, we developed a statistical method called PHet (Preserving Heterogeneity), which employs iterative subsampling and differential analysis of IQR combined with Fisher's method to identify a small set of features that preserve heterogeneity and enhance subtype clustering quality. Validation on public single-cell RNA-seq and microarray datasets demonstrated PHet's ability to maintain sample heterogeneity while distinguishing known disease/cell states, with a tendency to outperform previous differential expression and outlier-based methods. Furthermore, an analysis of a single-cell RNA-seq dataset from mouse tracheal epithelial cells identified two distinct basal cell subtypes differentiating towards a luminal secretory phenotype using PHet-based features, demonstrating promising results in a real-data application. These results highlight PHet's potential to enhance our understanding of disease mechanisms and cell differentiation, contributing significantly to the field of personalized medicine.

Introduction: The von Hippel-Lindau (VHL) E3 ubiquitin ligase has seen extensive research due to its involvement in the ubiquitin proteasome system and role as a tumor suppressor within the hypoxia signaling pathway. VHL has become an attractive target for proteolysis targeting chimeras (PROTACs), bifunctional molecules that can induce degradation of neo-substrate proteins. The development of VHL inhibitors and PROTACs has seen rapid development since disclosure of the first non-peptidic VHL ligand (2012).

Areas covered: Due to the demand for more diverse and sophisticated VHL ligands that can be applied to PROTACs, the number of patents disclosed has risen significantly in the past 5 years. Herein, the wide range of VHL modifications that have been patented since 2019 is covered. Specifically, any new or unique chemical modification to established VHL ligands or PROTACs will be discussed.

Expert opinion: The VHL chemical space continues to expand within the patent literature. There are exciting new modifications that can enhance the physiochemical properties of VHL PROTACs and other alterations can improve the affinity of the VHL ligand itself. Further optimization of the VHL chemical space will no doubt lead to the development of more VHL-based therapies and clinical candidates.