The present review focuses on the clinical translation of SINE drugs, especially selinexor (KPT-330), in hematologic and solid tumors, critically assesses the limitations of monotherapy and explores the mechanistic basis for synergistic combination strategies.
Abstract
Exportin 1 (XPO1) is a key nuclear export receptor that mediates the nuclear export of tumor suppressor proteins and growth-regulatory mRNAs from the nucleus to the cytoplasm. In several types of cancer, XPO1 is overexpressed or hyperactivated, leading to aberrant cytoplasmic sequestration of key tumor suppressors such as p53, p21, p73, FOXO and Rb. This mislocalization abrogates their nuclear transcriptional functions, disrupting cell cycle arrest, apoptosis and DNA repair, thereby promoting uncontrolled proliferation, survival and therapy resistance. Targeting XPO1 with selective inhibitors of nuclear export (SINE) has emerged as a promising anticancer strategy. The present review systematically examines the molecular mechanisms of XPO1-driven tumorigenesis and its rationale as a therapeutic target. The present review focuses on the clinical translation of SINE drugs, especially selinexor (KPT-330), in hematologic and solid tumors, critically assesses the limitations of monotherapy and explores the mechanistic basis for synergistic combination strategies. Ongoing clinical trials and future directions to optimize therapeutic efficacy are also highlighted. Collectively, the present review aims to provide a comprehensive foundation for advancing basic and clinical research on XPO1-targeted therapies.
Exportin 1 (XPO1/CRM1) is a clinically validated anticancer target whose inhibition blocks nuclear export and promotes cancer cell apoptosis. Current XPO1 inhibitors rely on covalent Michael addition to Cys528 in the nuclear export signal binding groove of XPO1. Here, we describe a novel XPO1 inhibitor, FR-027, that targets Cys528 through nucleophilic aromatic substitution. In contrast to clinical-stage XPO1 inhibitors selinexor and eltanexor, FR-027 acts reversibly and does not promote XPO1 protein degradation. Structural analysis of the XPO1-FR-027 complex reveals covalent modification of Cys528 and a closed-groove conformation that prevents degradation. FR-027 demonstrates potent on-target activity across multiple cancer cell types and delays disease progression while extending overall survival in xenograft and syngeneic models, including intracranial tumors. Notably, FR-027 does not induce significant thrombocytopenia, lymphopenia, or neutropenia in heavily treated mice. These findings underscore the distinct molecular and pharmacological properties of FR-027 and support its further evaluation for clinical development in diseases with significant unmet medical needs. XPO1 is a clinically validated anticancer target but inhibition with covalent drugs, such as selinexor, can cause significant toxicities. Here, the authors design and characterise FR-027, a reversible covalent inhibitor of XPO1 that does not induce XPO1 degradation, demonstrating strong antitumour activity, including in brain tumours, with an improved safety profile in mice.
Janne Van Hauwenhuyse, F. Reniers, L. Persoons et al.· Nature Communications· 0 citations
Emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment and immunotherapy response, positioning it as an increasingly attractive target for intervention.
Sheng-An Zheng, Cheng Wang, Xiao-Die Yao et al.· Drug Design, Development and...· 0 citations
BACKGROUND
Cyclin-dependent kinase 9 (CDK9) is a central regulator of RNA polymerase II elongation and has emerged as a therapeutic target in tumors characterized by transcriptional addiction. Growing interest in selective inhibitors and targeted degraders has renewed attention to the translational potential of CDK9-directed therapy.
AREAS COVERED
This review summarizes the molecular functions of the CDK9/positive transcription elongation factor b (P-TEFb) axis, its role in super-enhancer-driven oncogenic programs, and the mechanisms by which CDK9 inhibition promotes apoptosis, epigenetic derepression, and tumor microenvironment remodeling. We also discuss representative small-molecule inhibitors and proteolysis-targeting chimera (PROTAC) degraders, emerging biomarkers for patient stratification, rational combination strategies, and the current landscape of resistance mechanisms.
EXPERT OPINION
Selective targeting of CDK9 offers a promising route for treating refractory malignancies, particularly when guided by transcriptional dependency, biomarker-informed dosing, and rational combination design. Future progress will likely depend on improving therapeutic index, refining translational biomarkers, and anticipating adaptive resistance during clinical development.
Ti-Yao Liu, Zhongran Liu, Wen-Jing Wei et al.· Expert opinion on therapeuti...· 0 citations
This study elucidates a therapeutically targetable KPNB1-p65-Bcl-2 survival axis in multiple cancers and establishes a foundation for developing next-generation KPNB1 inhibitors.
Cong Li, Qiaohua Yan, Muhammad Muddasar Saeed et al.· Cell Chemical Biology· 0 citations
A review of the molecular characteristics and physiological functions of USP28, its context-dependent roles in neoplastic diseases, and its translational implications for targeted therapy and biomarker discovery highlights its potential as a therapeutic target for precision medicine.
Tongyong Luo, Shuncai Wu, Qing-Song Wang et al.· Frontiers in Immunology· 1 citation
Claudin 18.2 (CLDN18.2) is a functional subtype generated by alternative splicing of the CLDN18 gene. It is aberrantly overexpressed in a variety of gastrointestinal solid tumors such as gastric cancer and pancreatic cancer, and has emerged as a promising target for tumor targeted therapy. To date, zolbetuximab, a monoclonal antibody targeting CLDN18.2, has demonstrated survival benefits in phase III clinical trials. Antibody-drug conjugates, bispecific antibodies and chimeric antigen receptor T cell therapies also exhibit favorable application potential. Nevertheless, multiple challenges remain in this field. Distinction between CLDN18.1 and CLDN18.2 subtypes is often ambiguous, and the lack of unified immunohistochemistry testing criteria, including antibody selection and specimen types, leads to conflicting findings on prognostic research. Additionally, intratumoral heterogeneity, differential functions across tumor types and tumor microenvironment limitations further compromise the efficacy of targeted therapy. As a narrative review, this article systematically elaborates the molecular structure, expression regulatory mechanisms and clinicopathological value of CLDN18.2. Based on the data of 58 global clinical trials, it analyzes the current status, existing problems in testing standardization and drug development. Future directions are proposed, including standardizing detection protocols, developing differentiated drugs, optimizing combination regimens and overcoming drug resistance, aiming to provide references for the clinical translation and standardized application of CLDN18.2-targeted therapies.
