The nuclear export protein exportin‐1 in solid malignant tumours: From biology to clinical trials

Clinical and Translational Medicine, Год журнала: 2024, Номер 14(5)

Опубликована: Май 1, 2024

Abstract Background Exportin‐1 (XPO1), a crucial protein regulating nuclear‐cytoplasmic transport, is frequently overexpressed in various cancers, driving tumor progression and drug resistance. This makes XPO1 an attractive therapeutic target. Over the past few decades, number of available nuclear export‐selective inhibitors has been increasing. Only KPT‐330 (selinexor) successfully used for treating haematological malignancies, KPT‐8602 (eltanexor) haematologic tumours clinical trials. However, use inhibition expression yet to be thoroughly investigated studies outcomes solid tumours. Methods We collected numerous literatures explain efficacy Inhibitors preclinical wide range Results In this review, we focus on export function results from trials its malignant summarized mechanism action potential inhibitors, as well adverse effects response biomarkers. Conclusion emerged promising strategy fight against cancer, offering novel approach targeting tumorigenic processes overcoming SINE compounds have demonstrated tumours, ongoing research focused optimizing their use, identifying biomarkers, developing effective combination therapies. Key Points (XPO1) plays critical role mediating nucleocytoplasmic transport cell cycle. dysfunction promotes tumourigenesis resistance within The researches treatment Additional are essential address safety concerns identify biomarkers predicting patient inhibitors.

Язык: Английский

---

Selinexor in the treatment of liposarcoma: from preclinical evidence to clinical practice

Medical Oncology, Год журнала: 2025, Номер 42(4)

Опубликована: Март 8, 2025

Язык: Английский

---

Comparative oncology in action: vignettes on small molecule development

Veterinary oncology., Год журнала: 2025, Номер 2(1)

Опубликована: Апрель 15, 2025

Язык: Английский

---

Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer

Cancers, Год журнала: 2025, Номер 17(11), С. 1876 - 1876

Опубликована: Июнь 3, 2025

Metabolic enzymes and cancer-driving transcriptions factors are often overexpressed in neoplastic cells, their exposed cysteine residues amenable to chemical modification. This review explores alkylation as a cancer treatment strategy, focusing on Michael acceptors like curcumin helenalin, which interact with transcription NF-κB, STAT3 HIF-1α. Molecular docking studies using AutoDockFR revealed distinct binding affinities: showed strong interactions while helenalin exhibited high affinity for Synthetic compounds STAT3-IN-1 CDDO-Me demonstrated superior most targets, except HIF-1α, suggesting unique structural incompatibilities. Natural products such zerumbone umbelliferone displayed moderate activity, palbociclib highlighted synthetic-drug advantages. These results underscore the importance of ligand−receptor complementarity, particularly HIF-1α’s confined site, where helenalin’s terminal acceptor system proved optimal. The findings advocate integrating computational experimental approaches develop cysteine-targeted therapies, balancing synthetic precision natural product versatility context-dependent strategies.

Язык: Английский

---

Novel pharmacotherapies for the treatment of liposarcoma: a comprehensive update

Expert Opinion on Pharmacotherapy, Год журнала: 2024, Номер 25(17), С. 2293 - 2306

Опубликована: Ноя. 13, 2024

Liposarcomas are malignancies of adipocytic lineage and represent one the most common types soft tissue sarcomas. They encompass multiple histologies, each with unique molecular profiles. Treatment for localized disease includes resection, potentially perioperative radiation or systemic therapy. unresectable metastatic revolves around palliative therapy, which improved therapies urgently needed.

Язык: Английский

---

Exporting nuclear export inhibitors from hematologic to solid tumour malignancies

Clinical and Translational Discovery, Год журнала: 2024, Номер 4(4)

Опубликована: Июль 29, 2024

Exportin 1 (XPO1), formerly known as chromosomal region maintenance 1, belongs to the karyopherin family of proteins that are responsible for import and export macromolecules through nuclear pore complex. XPO1 is sole exporter hundreds cargoes including several RNA species key such tumor suppressors cell cycle proteins. Despite its essential housekeeping function in normal cells, their review, Lai et al note upregulation associated with a wide variety cancers, but not limited colorectal cancer, osteosarcoma, lung gastric ovarian glioma, pancreatic cancer oesophagal cancer.1 In non-cancer shuttles from nucleus cytoplasm while also regulating mitosis during interphase. After performing function, returns repeat process, making it vital part sustaining cellular physiological functions (Figure 1). However, increased expression leads imbalance nucleo-cytoplasmic transport. Though exact mechanisms overexpression solid cancers yet completely understood, chromosome 2p amplification accounts this subset hematologic neoplasms. Another means dysregulation found malignancies missense mutation E517K, which has been linked facilitating growth malignant B cells chronic lymphocytic leukaemia Hodgkin lymphoma.2 Clinical trials inhibitors have shown response rates ranging 26% 45% those advanced multiple myeloma, 28% rate relapsed or refractory diffuse large lymphoma.3-5 Due success, selinexor, first-in-class inhibitor Food Drug Administration-approved these two indications. This big question—can targeting be successful tumours? According al, promising, comes considerable challenges. The first were natural products irreversibly bound caused severe toxic side effects, leading discontinuation development anticancer therapies. response, small molecule designed slowly reversible more tolerable patients. Preclinical data suggests selinexor active tumours previous drug resistance vitro vivo induces apoptosis many cancerous lines prostate, bladder, renal carcinoma. While reducing tumour main goal preclinical studies, there questions dose dependency like sarcomas, may feasible humans clinical trials.6 diminish importance they can give us further insights. One study suggested KRAS mutant was dependent on line could handle buildup IκBα once inhibited, pinpointing critical mechanism action.7 Other studies show potential combination therapies, glioblastoma high synergistic effects bortezomib, dactinomycin, vinorelbine. With evidence, begun various tumours. al. describe results across types cancers. Currently, 58 different involving recruiting active, 35 completed trials. Of note, an open phase II trial success overall group reduction only 34% reporting adverse (AEs). groups given lowest per week had 10% having highest 6-month progression-free survival at 17.7%.8 gynaecological showed 38% reduction, 7% reaching partial about 7.4 months.9 A double-blind III endometrial underway (NCT03555422) if successful, lead approval tumors. On other hand, 16 so terminated due both failing meet expectations, emphasizing need possibly research into inhibitors, second-generation eltanexor. So far, eltanexor less blood-brain barrier penetration weight loss animal models when compared currently going under I see patients (NCT02649790). Felezonexor, another inhibitor, determine well dosage specifically (NCT02667873), showing best stable disease.10 Given above, worth continuing pursue tumours; however, ratio future targeted populations most likely respond inhibition. obstacle grapple AEs, needed find minimum efficacy. minimal low-effective then added treatments synergetic effects. Further allow better understanding benefit treatment. Alexandra Chirino Justin Taylor conceptualized manuscript. Alyssa Maye wrote draft revised final All authors approve draft. We would thank Dr. Sana Chaudhry her advice supported by National Institute General Medical Sciences (NIGMS)/NIH (R35GM151109), Doris Duke Charitable Foundation, Edward P. Evans Foundation NCI Cancer Center Support Grant Sylvester Comprehensive (P30CA240139). declare no conflict interest. Not applicable.

Язык: Английский

---

Advances in the role of membrane-bound transcription factors in carcinogenesis and therapy

Discover Oncology, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 15, 2024

Protein shuttling between the cytoplasm and nucleus is a unique phenomenon in eukaryotic organisms, integral to various cellular functions. Membrane-bound transcription factors (MTFs), specialized class of nucleocytoplasmic proteins, are anchored cell membrane enter upon ligand binding exert their transcriptional regulatory MTFs crucial signal transduction, aberrant closely associated with tumor initiation, progression, resistance anticancer therapies. Studies have demonstrated that MTFs, such as human epidermal growth factor receptor (HER), fibroblast (FGFR), β-catenin, Notch, insulin-like 1 (IGF-1R), insulin (IR), play critical roles tumorigenesis cancer progression. Targeted therapies developed against HERs FGFRs, among these yielded significant success treatment. However, development drug remains major challenge. As research on progress, it anticipated additional MTF-targeted will be enhance In this review, we summarized recent advancements study carcinogenesis therapy, aiming provide valuable insights into potential targeting MTF pathways for reseach therapeutic strategies.

Язык: Английский

---

Discovery of Novel XPO1 PROTAC Degraders for the Treatment of Acute Myeloid Leukemia

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 283, С. 117182 - 117182

Опубликована: Дек. 17, 2024

Язык: Английский

---