Unraveling the Role of Repurposed Drugs in the Treatment of Acne: Success so Far and the Road AheadKumbhar, Popat S.; Kamble, Vikas; Kolekar, Kaustubh Ajit; Vishwas, Sukriti; Kumbhar, Pranav; Patil, Kalpana S.; Gupta, Gaurav; Kharabe, Pankaj M.; Singh, Manisha; Gurav, Shailendra; Chellappan, Dinesh Kumar; Singh, Sachin Kumar; Dua, Kamal; Disouza, John; Patravale, Vandana
doi: 10.1002/ddr.70057pmid: 39925109
Acne is a skin disease that impacts 9.4% of the world's population. Available treatments for managing acne include retinoid‐like drugs, antibiotics, corticosteroids, photo, and radiotherapy. Howevere, the aforementioned treatments have certain limitations such as possibility of developing skin cancer from tetracycline, doxycycline, and corticosteroids, microbial resistance to antibiotics, and deadly side effects, and so forth. Repurposing of existing therapeutics having excellent safety profile can be promising way to treat acne efficiently. The repurposed drugs and phytoceuticals from diverse classes have demonstrated promising effects in treating acne. These repurposed drugs have displayed antiacne effectiveness by targeting single or multiple signaling pathways. Various repurposed therapeutics undergoing clinical trials at different phases demonstrated their safety and efficacy in treating acne. Despite being a very good, safe, and less time‐consuming strategy, drug repurposing (DR) faces multiple challenges such as lack of regulatory guidelines, preservation of intellectual property, and clinical validation of claimed therapeutic indication. DR appears to be a viable approach and is likely to offer effective treatment at a reasonable cost in alleviating acne.
Current Strategies and Future Dimensions in the Development of KRAS Inhibitors for Targeted Anticancer TherapyD'Alessio‐Sands, Laura; Gaynier, Joshua; Michel‐Milian, Victoria; Agbowuro, Ayodeji A.; Brackett, Christopher M.
doi: 10.1002/ddr.70042pmid: 39799558
KRAS is a proto‐oncogene that is found to be mutated in 15% of all metastatic cancers with high prevalence in pancreatic, lung, and colorectal cancers. Additionally, patients harboring KRAS mutations respond poorly to standard cancer therapy. As a result, KRAS is seen as an attractive target for targeted anticancer therapy. Over the last decade, this protein has evolved from being termed “undruggable” to producing two clinically approved drugs along with several more in clinical development, and many under preclinical investigations. This review details the development of various KRAS‐targeted molecules with emphasis on the different drug design strategies employed by examining the following areas: (1) Direct inhibition of KRAS mutants using small molecule binders, (2) Inhibiting the activated state of KRAS mutants using a binary complex of small molecule binders and cyclophilin A, and (3) Targeted degradation of KRAS mutants using the PROTAC approach. We assess the pharmacological attributes and possible clinical benefits of the different molecules and look to the next frontiers in the application of KRAS inhibitors as anticancer agents.
An Inducible Neural Stem Progenitor Cell Model for Testing Therapeutic Interventions Against Neurodegeneration FENIBGiustini, Alessandro; Maiocchi, Alice; Serangeli, Ilaria; Pedrini, Martina; Quintiliani, Anna; Sabato, Valentina; Bonato, Francesca; Seneci, Pierfausto; Lupo, Giuseppe; Passarella, Daniele; Miranda, Elena
doi: 10.1002/ddr.70041pmid: 39749681
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a neurodegenerative pathology caused by accumulation of mutant neuroserpin (NS) polymers inside the endoplasmic reticulum (ER) of neurons, leading to cellular toxicity and neuronal death. To date, there is no cure for FENIB, and only palliative care is available for FENIB patients, underlining the urgency to develop therapeutic strategies. The purpose of this work was to create a cellular system designed for testing small molecules able to reduce the formation of NS polymers. Our results show the generation and characterisation of a novel cell culture model for FENIB based on neural stem progenitor cells (NPCs) with inducible expression of either wild type (WT) or G392E NS, a variant that causes severe FENIB. We also report the use of these novel cell lines to explore the effects of four different proteolysis targeting chimaera (PROTAC) compounds, small bivalent molecules engineered to bind to the E3 ubiquitin ligase cereblon, and to NS through a recruiting motif based on the small molecule embelin. This approach aims to enhance the degradation of mutant NS after retro‐translocation to the cytosol by facilitating its targeting to the proteasome. Our results show little toxicity and no variation in NS levels with any of the compounds tested. In conclusion, this work sets the basis for future attempts to identify molecules able to prevent NS accumulation inside the ER of cultured cells.
Exosomal ALKBH5 Alleviates Vascular Calcification by Suppressing Cell Apoptosis via m6A‐Modified GSDMEXu, Guian; Li, Qingman; Zhu, Lijie; Yang, Tingjie; Yang, Yapan; Yang, Honghui
doi: 10.1002/ddr.70065pmid: 39950329
This study aimed to explore the function and regulatory mechanism of ALKBH5 in the progression of coronary artery calcification. Human aortic vascular smooth muscle cells (HA‐VSMCs) were treated with inorganic phosphate (Pi) and exosomes derived from bone marrow mesenchymal stem cell (BMSC) carrying ALKBH5, a GSDME overexpression vector or si‐GSDME. The morphology and size of the exosomes were assessed using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Calcium deposition was measured using Alizarin red staining and cell pyroptosis was evaluated using Hoechst 33342/PI staining. The association between ALKBH5 and m6A modifications was confirmed by methylated‐RNA immunoprecipitation assay (MeRIP) and dot blot assays. The expression levels of ALKBH5 and GSDME were quantified by quantitative real‐time polymerase chain reaction (qRT‐PCR), and protein levels were quantified by western blot. BMSCs‐derived exosomes reduced calcium deposition and cell pyroptosis in Pi‐treated HA‐VSMCs. Exosomes containing ALKBH5 overexpression inhibited high mobility group box 1 (HMGB1) and cell apoptosis, thereby promoting vascular calcification, whereas ALKBH5 knockdown in exosomes exerted the opposite effect on calcification development. Additionally, ALKBH5 was found to regulate the m6A modification of GSDME. Overexpression of GSDME reversed the effects of ALKBH5 in exosomes on HMGB1 expression and cell apoptosis. Exosomal ALKBH5 mitigated HMGB1 expression and cell pyroptosis by modulating the m6A modification of GSDME, thus influencing the progression of coronary artery calcification.
Phthalazine Derivatives as VEGFR‐2 Inhibitors: Docking, ADMET, Synthesis, Design, Anticancer Evaluations, and Apoptosis InducersBayoumi, Hatem Hussein; Ibrahim, Mohamed‐Kamal; Dahab, Mohammed A.; Khedr, Fathalla; El‐Adl, Khaled
doi: 10.1002/ddr.70037pmid: 39717939
New phthalazine‐derived inhibitors for VEGFR‐2 were synthesized for anticancer evaluations. Also, docking studies were performed to explore the suggested binding orientations of the novel derivatives inside the binding site of VEGFR‐2. The achieved biological data were extremely interrelated to that of docking study. In specific, derivative 3f was the greatest effective compound against HepG2 and MCF‐7 cancer cell lines with IC50 = 0.17 ± 0.01 and 0.08 ± 0.01 µM individually. The six highly active derivatives 3b, 3e, 3f, 3g, 6a, and 6b were estimated for their VEGFR‐2 inhibitory effects. Derivative 3f was the greatest effective compound which inhibited VEGFR‐2 at IC50 = 0.0557 ± 0.002 µM. The activities of 3f were assessed against MCF‐7 cancer cells for apoptosis induction, cell cycle distribution, and growth inhibition. Compound 3f induced early apoptosis (21.44%) by more than 36 folds over the control (0.59%). The obtained results showed that compound 3f induced necrotic effect (6.03%) by more than threefolds over the control (1.75%). On the other hand, compound 3f improved the level of the pro‐apoptotic protein; Bax by approximately fivefolds. Moreover, compound 3f noticeably decreased the levels of the anti‐apoptotic proteins Bcl‐2 by nearly fourfolds in comparison to the control. In addition, derivative 3f remarkably enhanced the Bax/Bcl2 ratio by nearly 18 folds, as compared to the control. Finally, our derivatives 3f, 3g, and 6b revealed good in silico considered ADMET profile in comparing to sorafenib.
Naringenin Inhibits Ferroptosis in Renal Tubular Epithelial Cells of Diabetic Nephropathy Through SIRT1/FOXO3a Signaling PathwayZhou, Yi; Hu, Tianchi; Zeng, Huarong; Lin, Lin; Xie, Huan; Lin, Rong; Huang, Mengya
doi: 10.1002/ddr.70044pmid: 39799560
Naringenin has the potential to regulate ferroptosis and mitigate renal damage in diabetic nephropathy (DN). However, it remains unclear whether the naringenin's effects in DN are linked to its ability to regulate ferroptosis. This study investigated the potential anti‐ferroptosis properties of naringenin in high glucose (HG)‐induced renal tubular epithelial cell models. HK‐2 cells were cultured in HG medium to establish the DN cell model. HK‐2 cells were treated with different doses of naringenin to explore the effect of naringenin. The CCK‐8 results show that 50 μM ~ 200 μM of naringenin do not affect the viability of HK‐2 cells and the viability of HG‐induced HK‐2 cells increase in a dose‐dependent manner with naringenin treatment. Additionally, naringenin increased the levels of IL‐10 while decreasing the levels of IL‐1β, TNF‐α, IL‐6, and ROS in HG‐induced HK‐2 cells. Naringenin also reduced the levels of Fe2+, oxidized lipid ROS, MDA, 4‐HNE, ACSL4, and TFR1 in HG‐induced HK‐2 cells, while increasing the levels of non‐oxidized lipid ROS, SOD, GSH‐Px, SLC7A11, and GPX4. Meanwhile, naringenin restored the levels of MMP, ATP and MPTP opening, reduced OCR in HG‐induced HK‐2 cells. Furthermore, naringenin reversed the decreased expression of SIRT1, p‐FOXO3a, Nrf2 and Nuclear Nrf2 caused by HG. SIRT1 inhibitor EX527 and Nrf2 inhibitor ML385 attenuated the effects of naringenin on ferroptosis in HG‐induced HK‐2 cells, with EX527 demonstrating a stronger reversal effect on ferroptosis than ML385. These results suggest that naringenin inhibits ferroptosis in HG‐induced HK‐2 cells mainly through SIRT1/FOXO3a signaling pathway. This finding further enhanced our understanding of the mechanism behind naringenin's protective effect on DN.
Antileishmanial and Antitrypanosomal Trends of Synthetic Tetralone DerivativesAlkhaldi, Abdulsalam A. M.; Koning, Harry P.; Bukhari, Syed Nasir Abbas
doi: 10.1002/ddr.70055pmid: 39878094
Leishmaniasis and trypanosomiasis are parasitic diseases that are closely linked to poverty, pose significant local burdens, and are common in tropical and subtropical regions. Various synthetic tetralone derivatives were studied as potential scaffolds for antileishmanial and antitrypanosomal activities. The compounds were studied for their effectiveness against multiple kinetoplastid protozoan pathogens: Leishmania major, Leishmania mexicana, and bloodstream trypomastigotes of Trypanosoma brucei brucei. Two different strains of T. b. brucei were used. The first strain was the wild‐type Trypanosoma brucei (s427‐WT), and the second strain was the multidrug resistant (MDR) strain B48, which was produced by deleting the TbAT1 gene from s427WT and subsequent adaptation to high levels of resistance to diamidines and organo‐arsenical drugs. Compounds 4c, 7c, 9b, and 11b showed activity against two strains of Trypanosoma and two different Leishmania species, establishing them as versatile leads with broad anti‐kinetoplastid activity. Compound 4c, a tetralone derivative with a bromo‐containing trimethoxybenzylidene moiety and methyl‐substituted cyclohexanone ring, was identified as the most potent inhibitor for both T. b. brucei strains, with EC50 values of 0.19 and 0.22 µM for WT and B48, respectively, showing the absence of cross‐resistance with the diamidine and arsenical trypanocide classes. In addition, compound 4c exhibited more potency than both controls, eflornithine and pentamidine, against the MDR strain. We conclude that tetralone derivates could be a valuable starting point for the discovery of new antiparasitic drugs.