PROTAC unleashed: Unveiling the synthetic approaches and potential therapeutic applications

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 279, С. 116837 - 116837

Опубликована: Сен. 10, 2024

Язык: Английский

---

Histamine N-methyltransferase (HNMT) as a potential auxiliary biomarker for predicting adaptability to anti-HER2 drug treatment in breast cancer patients

Biomarker Research, Год журнала: 2025, Номер 13(1)

Опубликована: Янв. 9, 2025

Abstract Background Up to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that with low HER2 expression and metastatic had positive response trastuzumab-deruxtecan (T-Dxd). This indicates relying solely on as single diagnostic marker predict the efficacy anti-HER2 drugs is insufficient. study highlights interaction between histamine N-methyltransferase (HNMT) an adjunct predictor for response. Furthermore, modulation by HNMT may explain why those still respond T-Dxd. Methods We investigated impact protein therapy in both vivo ex models patient-derived xenografts cell line-derived xenografts. Our analysis included Förster resonance energy transfer (FRET) assess strength proteins trastuzumab-resistant sensitive tumor tissues. Additionally, we used fluorescence lifetime imaging microscopy (FLIM), cleaved luciferase, immunoprecipitation dynamics HER2. evaluated influence activity binding antibodies their targets through flow cytometry. also observed nuclear translocation HNMT/HER2-ICD cells using fluorescent double staining DeltaVision microscopy. Finally, ChIP sequencing was employed identify target genes affected complex. Results potential auxiliary biomarker diagnosing + cancer. FRET demonstrated significant trastuzumab-sensitive tissue ( n = 50), suggesting treatment Mechanistic studies revealed contributes increased at transcriptional level, thereby impacting therapy. subset triple-negative cancers characterized overexpression be antibody–drug conjugates such Conclusions These findings offer crucial insights clinicians evaluating candidates therapy, especially HER2-low who could gain from T-Dxd Identifying help pinpoint would benefit

Язык: Английский

---

Effects of BYL-719 (alpelisib) on human breast cancer stem cells to overcome drug resistance in human breast cancer

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Окт. 14, 2024

Introduction Breast cancer continues to be a major health concern and is currently the most commonly diagnosed worldwide. Relapse, metastasis, therapy resistance are clinical issues that doctors need address. We believe BYL-719, which PI3 kinase p110а inhibitor, could also inhibit breast stem cell phenotype epithelial-to-mesenchymal transition (EMT). In addition PI3K/AKT signaling pathway, BYL-719 can essential cancer-related pathways, all of would ultimately act on microenvironment cells, quite complicated regulates characteristics tumors. These include stemness malignant tumors, plasticity anti-apoptotic features. Materials methods A three-dimensional (3D) mammosphere culture method was used in vitro collect cells (BCSCs). MTT, clonogenic, apoptosis assays were detect viability, self-renewal, differentiation abilities. sphere formation assay under 3D conditions mammophore inhibition rate BYL-719. The subpopulation CD44 + CD24 − detected using flow cytometry analysis while EMT biomarkers pathways western blotting. All data analyzed GraphPad Prism 9 software. Results BCSC-like obtained by . confirmed proliferation cultures inhibited. PI3K/AKT/mTOR pathway inhibited Notch, JAK-STAT MAPK/ERK have crosstalk tumor (TME) By comparing eribulin-resistant lines, we effectively overcome drug resistance. Summary/conclusion novel highly effective for enriching BCSCs Furthermore, acting various pathways. Finally, targeting BCSCs. Conjugation with other anti-neoplastic agents may promising treatment this clinic.

Язык: Английский

---

The Potential of PARP Inhibitors as Antitumor Drugs and the Perspective of Molecular Design

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 68(1), С. 18 - 48

Опубликована: Дек. 26, 2024

PARP (poly-ADP ribose polymerase) has received widespread attention in cancer treatment. Research shown that plays a crucial role DNA damage repair and become popular target for drug design. Based on the mechanism of "synthetic lethality", multiple PARPis (PARP inhibitors) have been launched treatment BRCA deficient tumors. For example, approved significant potential treatment, particularly breast cancers associated with BRCA1/BRCA2 deficiencies. However, clinical efficacy safety inhibitors different remain issues cannot be overlooked. The design aims to eliminate their resistance broaden application scope. Designing selective PARP-1 is also strategy. PROTACs (Proteolysis Targeting Chimeras) degrade novel

Язык: Английский

---

Exosome-mediated intercellular communication and PROTACs delivery: A Dual Approach for Precision Therapy in Colon Cancer

Journal of Drug Delivery Science and Technology, Год журнала: 2024, Номер unknown, С. 106596 - 106596

Опубликована: Дек. 1, 2024

Язык: Английский

---