bims-midomi 2025-11-02 papers

Biomed Pharmacother. 2025 Oct 24. pii: S0753-3322(25)00880-7. [Epub ahead of print]192 118686

Serdemetan promotes bone regeneration via coordinated regulation of osteoblast and osteoclast activity.

Sol Jeong, Seung-Chan An, Hyun-Ju An, Sungjoon Lim, Jin Man Kim, Soonchul Lee.

Although murine double minute 2 (MDM2) inhibitors are known for their anti-cancer effects via p53 activation, their potential role in bone regeneration remains largely unexplored. In this study, we systematically screened 22 MDM2 inhibitors and identified serdemetan as the best candidate according to its dual functionalities of promoting osteogenesis and inhibiting osteoclastogenesis. Therefore, we adopted a drug repurposing study to determine the impact of MDM2 pharmacological inhibition on osteogenic and osteoclast activities in vitro and in vivo. Specifically, we validated the pro-osteogenic and anti-osteoclastic effects of serdemetan using human bone marrow stromal cells (hBMSCs) and bone marrow-derived macrophages (BMM), then integrated bulk RNA-sequencing data to elucidate the possible molecular mechanisms underlying biomineralization. Serdemetan significantly enhanced osteogenic differentiation and mineralization in hBMSCs and potently suppressed osteoclast formation, actin ring assembly, and bone resorption in BMMs. Transcriptomic profiling revealed robust activation of the p53 signaling pathway and upregulation of osteogenic genes in hBMSCs. Moreover, serdemetan downregulated osteoclast-related markers and enhanced autophagy-associated gene expression in BMMs, suggesting a p53-mediated mechanism of dual regulation. Regarding preclinical efficacy, serdemetan markedly accelerated bone healing in a rat calvarial defect model and restored trabecular bone architecture in an ovariectomy-induced osteoporosis model, demonstrating similar therapeutic efficacy to alendronate. In summary, we present serdemetan as a promising candidate for bone regeneration through regulation of the MDM2-p53 axis, offering new therapeutic possibilities beyond its established role in oncology.

Keywords: Bone regeneration; Drug repurposing; MDM2–p53 signaling; Osteoclastogenesis; Osteogenesis; Serdemetan

DOI: https://doi.org/10.1016/j.biopha.2025.118686

Front Pharmacol. 2025 ;16 1663766

Targeting MDM2, RAS, and PCNA for cancer targeted therapy: pan-cancer approaches vs. cancer-specific strategies.

Wei Wang, Abigail Alley, Na Sun, Meheret Tadesse, Xinshi Wang, Ruiwen Zhang.

Cancer therapy and cancer drug discovery and development have been historically focused on specific cancers (tissue/organ of origin). However, with advances in molecular biology and multi-omics of cancer, there is a trend to develop pan-cancer therapeutic modalities. In targeted therapy, pan-cancer strategies target common molecular alterations across different cancer types and specific cancer strategies are tailored to the unique biological characteristics of individual tumor types. Each approach offers distinct advantages and limitations, and understanding these differences is critical in the era of precision oncology. Targeting key molecular drivers in cancer has significantly changed drug development, allowing for broad-spectrum therapeutic strategies that address shared oncogenic pathways across various tumor types. Among these drivers, RAS, PCNA, and MDM2 have become critical targets due to their roles in a broad-spectrum of cancer biology, e.g., cell proliferation, survival, and genomic stability. Advances in molecularly guided therapies have led to promising approaches for disrupting these pathways, offering new opportunities for cancer treatment. Despite significant progress in the past, challenges such as drug resistance, tumor heterogeneity, and toxicity remain obstacles to widespread clinical success. This review explores the historical development, current advancements, and future directions of RAS, PCNA, and MDM2-targeted therapies, emphasizing their potential to reshape cancer treatment through pan-cancer approaches using biomarker-driven technologies, combination strategies, and next-generation inhibitors. These advancements pave the way for more effective and durable therapies across a wide range of malignancies.

Keywords: MDM2; PCNA; Ras; cancer-specific; pan-cancer

DOI: https://doi.org/10.3389/fphar.2025.1663766

Pharmaceuticals (Basel). 2025 Oct 07. pii: 1502. [Epub ahead of print]18(10):

Design and Optimization of Spiro-Isatin-Thiazolidinone Hybrids with Promising Anticancer Activity.

Dmytro Khylyuk, Serhii Holota, Natalia Finiuk, Rostyslav Stoika, Tetyana Rumynska, Roman Lesyk.

Background: Cancer remains a leading cause of morbidity and mortality worldwide, and current therapies are limited by toxicity, cost, and resistance. Inhibition of the MDM2-p53 interaction is a promising anticancer strategy, as this pathway is frequently dysregulated across tumors. Spiro-isatin-thiazolidinone derivatives have shown diverse biological activities, including anticancer effects, but require optimization to improve potency and selectivity. The aims were to design, synthesize, and evaluate novel spiro-isatin-thiazolidinone hybrids with enhanced cytotoxicity against cancer cells and reduced toxicity toward normal cells. Methods: Derivatives were designed using molecular docking against MDM2, followed by structural optimization. Cytotoxic activity was evaluated in vitro by MTT assays on human and murine cancer cell lines and pseudo-normal cells. Docking and 100 ns molecular dynamics simulations assessed binding stability, while ADMET properties were predicted in silico. Results: Several derivatives exhibited micromolar cytotoxicity, with compound 18 emerging as the most potent and selective candidate (IC50 6.67-8.37 µM across most cancer lines; >100 µM in HaCaT). Docking showed a strong affinity for MDM2 (-10.16 kcal/mol), comparable to the reference ligand, and stable interactions in simulations. ADMET predictions confirmed good oral bioavailability and moderate acute toxicity, fully compliant with Lipinski's Rule of Five. Overall, the newly synthesized spiro-isatin-thiazolidinone hybrids, particularly compound 18, demonstrated potent and selective anticancer activity, favorable pharmacokinetic properties and a good toxicity profile.

Keywords: MDM2–p53 interaction; drug design; molecular docking; spiro-isatin-thiazolidinone hybrids

DOI: https://doi.org/10.3390/ph18101502

Discov Oncol. 2025 Oct 27. 16(1): 1970

Advances in polycythemia vera treatment with targeted therapies and clinical trials.

Doaa Hassanien, Rashid A AlYafei, Omar H Metwally, Izzaldin Alremawi, Abdulla Khalid Al-Kaabi, Mohamed Elahtem, Talal Al-Sayed, Mohamed A Yassin.

Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by excessive red blood cell production, leading to a heightened risk of thrombosis, hemorrhage, and progression to myelofibrosis. While traditional therapies such as phlebotomy and hydroxyurea have been used for disease management, they do not address the underlying pathophysiology or alleviate common symptoms like fatigue and pruritus. Recent advances in targeted therapies offer promising new options for PV treatment. This review explores novel therapeutic approaches currently under investigation, including hepcidin agonists, MDM2 inhibitors, histone deacetylase (HDAC) inhibitors, and LSD1 inhibitors. These therapies aim to correct hematopoietic dysregulation, reduce symptom burden, and improve long-term outcomes for PV patients. While clinical trials show encouraging results, further studies are needed to fully evaluate their safety, efficacy, and potential for broad clinical use. Ultimately, these emerging treatments could reshape the landscape of PV management by offering more personalized, effective options for patients.

Keywords: Chronic myeloproliferative disorder (CMD); Clinical trials; Hepcidin agonists; Histone deacetylase (HDAC) inhibitors; LSD1 inhibitors; MDM2 inhibitors; Polycythemia vera (PV)

DOI: https://doi.org/10.1007/s12672-025-03703-9