Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with no effective treatment, particularly in the advanced stage. This study explored the antiproliferative activity of khasianine against pancreatic cancer cell lines of human (Suit2-007) and rat (ASML) origin. Khasianine was purified from Solanum incanum fruits by silica gel column chromatography and analyzed by LC-MS and NMR spectroscopy. Its effect in pancreatic cancer cells was evaluated by cell proliferation assay, chip array and mass spectrometry. Proteins showing sensitivity to sugars, i.e. sugar-sensitive lactosyl-Sepharose binding proteins (LSBPs), were isolated from Suit2-007 cells by competitive affinity chromatography. The eluted fractions included galactose-, glucose-, rhamnose- and lactose-sensitive LSBPs. The resulting data were analyzed by Chipster, Ingenuity Pathway Analysis (IPA) and GraphPad Prism. Khasianine inhibited proliferation of Suit2-007 and ASML cells with IC50 values of 50 and 54 μg/mL, respectively. By comparative analysis, khasianine downregulated lactose-sensitive LSBPs the most (126%) and glucose-sensitive LSBPs the least (85%). Rhamnose-sensitive LSBPs overlapped significantly with lactose-sensitive LSBPs and were the most upregulated in data from patients (23%) and a pancreatic cancer rat model (11.5%). From IPA, the Ras homolog family member A (RhoA) emerged as one of the most activated signaling pathways involving rhamnose-sensitive LSBPs. Khasianine altered the mRNA expression of sugar-sensitive LSBPs, some of which were modulated in data from patients and the rat model. The antiproliferative effect of khasianine in pancreatic cancer cells and the downregulation of rhamnose-sensitive proteins underscore the potential of khasianine in treating pancreatic cancer.

Oleanolic acid (OA), a common pentacyclic triterpenoid found in plants, has several therapeutic uses, including the treatment of hepatopathy disorders. However, due to OA’s weak permeability and limited bioavailability, its therapeutic advantages are limited. Here, we showed that a short peptide known as p10 not only binds to OA but also rapidly enhances OA delivery into cultured hepatic stellate cells (HSCs), lowers their synthesis of fibrogenic proteins, and further reduces the HSC migration capacity. Our findings show that noncovalently conjugating short peptides to OA improves its pharmacological efficacy and permeability.

Primitive data organization practices struggle to deliver at the scale and consistency required to meet multidisciplinary collaborations in drug discovery. For effective data sharing and coordination, a unified platform that can collect and analyze scientific information is essential. We present DAIKON, an open-source framework that integrates targets, screens, hits, and manages projects within a target-based drug discovery portfolio. Its knowledge capture components enable teams to record subsequent molecules as their properties improve, facilitate team collaboration through discussion threads, and include modules that visually illustrate the progress of each target as it advances through the pipeline. It serves as a repository for scientists sourcing data from Mycobrowser, UniProt, PDB. The goal is to globalize several variations of the drug-discovery program without compromising local aspects of specific workflows. DAIKON is modularized by abstracting the database and creating separate layers for entities, business logic, infrastructure, APIs, and frontend, with each tier allowing for extensions. Using Docker, the framework is packaged into two solutions: daikon-server-core and daikon-client. Organizations may deploy the project to on-premises servers or VPC. Active-Directory/SSO is supported for user administration. End users can access the application with a web browser. Currently, DAIKON is implemented in the TB Drug Accelerator program (TBDA).

This article references 34 other publications. This article has not yet been cited by other publications. This article references 34 other publications.

In sepsis, plasma lactate is a key biomarker of disease severity, prognosis, and treatment success. However, the median time to result for clinical lactate tests is 3 h. We recently reported a near-infrared fluorescent (NIRF) blood lactate assay that relies on a two-step enzymatic reaction in a liposomal reaction compartment. This assay was optimized in human blood and was capable of quantifying lactate in fresh capillary blood from human volunteers at clinically relevant concentrations in 2 min. However, these studies were performed with a tabletop fluorescence plate reader. For translation to the point of care, the liposomal lactate assay needs to be combined with a small portable NIR fluorometer. Portable NIR fluorometers were successfully used for the analysis of skin and soil samples, but reports for blood metabolite assays are scarce. We aimed at testing the performance of the liposomal lactate assay in combination with a commercial small portable NIR fluorometer. First, we tested the fluorophore of the liposomal lactate assay using the NIR dye sulfo-cyanine 7; we observed strong fluorescence signals and high linearity. Second, we performed the liposomal lactate assay in lactate-spiked human arterial blood using the portable fluorometer as the detector and observed strong and highly linear lactate sensing at clinically relevant lactate concentrations after 2 min. Finally, spiking fresh mouse blood with three clinically relevant lactate concentrations led to a significantly different response to all three concentrations after 5 min. These results highlight the usefulness of the tested portable NIR fluorometer for the liposomal lactate assay and motivate a clinical evaluation of this rapid and easy-to-use lactate assay.

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which was identified in Wuhan, China in December 2019 and jeopardized human lives. It spreads at an unprecedented rate worldwide, with serious and still-unfolding health conditions and economic ramifications. Based on the clinical investigations, the severity of COVID-19 appears to be highly variable, ranging from mild to severe infections including the death of an infected individual. To add to this, patients with comorbid conditions such as age or concomitant illnesses are significant predictors of the disease’s severity and progression. SARS-CoV-2 enters inside the host cells through ACE2 (angiotensin converting enzyme2) receptor expression; therefore, comorbidities associated with higher ACE2 expression may enhance the virus entry and the severity of COVID-19 infection. It has already been recognized that age-related comorbidities such as Parkinson’s disease, cancer, diabetes, and cardiovascular diseases may lead to life-threatening illnesses in COVID-19-infected patients. COVID-19 infection results in the excessive release of cytokines, called “cytokine storm”, which causes the worsening of comorbid disease conditions. Different mechanisms of COVID-19 infections leading to intensive care unit (ICU) admissions or deaths have been hypothesized. This review provides insights into the relationship between various comorbidities and COVID-19 infection. We further discuss the potential pathophysiological correlation between COVID-19 disease and comorbidities with the medical interventions for comorbid patients. Toward the end, different therapeutic options have been discussed for COVID-19-infected comorbid patients.

The ProTide prodrug design is a powerful tool to improve cell permeability and enhance the intracellular activation of nucleotide antiviral analogues. Previous in vitro studies showed that the activation of ProTide prodrugs varied in different cell lines. In the present study, we investigated the activation profiles of two antiviral prodrugs tenofovir alafenamide (TAF) and sofosbuvir (SOF) in five cell lines commonly used in antiviral research, namely, Vero E6, Huh-7, Calu-3, A549, and Caco-2. We found that TAF and SOF were activated in a cell-dependent manner with Vero E6 being the least efficient and Huh-7 being the most efficient cell line for activating the prodrugs. We also demonstrated that TAF was activated at a significantly higher rate than SOF. We further analyzed the protein expressions of the activating enzymes carboxylesterase 1, cathepsin A, histidine triad nucleotide-binding protein 1, and the relevant drug transporters P-glycoprotein and organic anion-transporting polypeptides 1B1 and 1B3 in the cell lines using the proteomics data extracted from the literature and proteome database. The results revealed significant differences in the expression patterns of the enzymes and transporters among the cell lines, which might partially contribute to the observed cell-dependent activation of TAF and SOF. These findings highlight the variability of the abundance of activating enzymes and transporters between cell lines and emphasize the importance of selecting appropriate cell lines for assessing the antiviral efficacy of nucleoside/nucleotide prodrugs.

Diabetes mellitus (DM) and its associated complications are considered one of the major health risks globally. Among numerous complications, diabetic cardiomyopathy (DCM) is characterized by increased accumulation of lipids and reduced glucose utilization following abnormal lipid metabolism in the myocardium along with oxidative stress, myocardial fibrosis, and inflammation that eventually result in cardiac dysfunction. The abnormal metabolism of lipids plays a fundamental role in cardiac lipotoxicity following the occurrence and development of DCM. Recently, it has been revealed that cannabinoid type-2 (CB2) receptors, an essential component of the endocannabinoid system, play a crucial role in the pathogenesis of obesity, hyperlipidemia, and DM. Provided the role of CB2R in regulating the glucolipid metabolic dysfunction and its antioxidant as well as anti-inflammatory activities, we carried out the current study to investigate the protective effects of a selective CB2R agonist, β-caryophyllene (BCP), a natural dietary cannabinoid in the murine model of DCM and elucidated the underlying pharmacological and molecular mechanisms. Mice were fed a high-fat diet for 4 weeks followed by a single intraperitoneal injection of streptozotocin (100 mg/kg) to induce the model of DCM. BCP (50 mg/kg body weight) was given orally for 12 weeks. AM630, a CB2R antagonist, was given 30 min before BCP treatment to demonstrate the CB2R-dependent mechanism of BCP. DCM mice exhibited hyperglycemia, increased serum lactate dehydrogenase, impaired cardiac function, and hypertrophy. In addition, DCM mice showed alternations in serum lipids and increased oxidative stress concomitant to reduced antioxidant defenses and enhanced cardiac lipid accumulation in the diabetic heart. DCM mice also exhibited activation of TLR4/NF-κB/MAPK signaling and triggered the production of inflammatory cytokines and inflammatory enzyme mediators. However, treatment with BCP exerted remarkable protective effects by favorable modulation of the biochemical and molecular parameters, which were altered in DCM mice. Interestingly, pretreatment with AM630 abrogated the protective effects of BCP in DCM mice. Taken together, the findings of the present study demonstrate that BCP possesses the capability to mitigate the progression of DCM by inhibition of lipotoxicity-mediated cardiac oxidative stress and inflammation and favorable modulation of TLR4/NF-κB/MAPK signaling pathways mediating the CB2R-dependent mechanism.

The Notch pathway is remarkably simple without the interventions of secondary messengers. It possesses a unique receptor–ligand interaction that imparts signaling upon cleavage of the receptor followed by the nuclear localization of its cleaved intracellular domain. It is found that the transcriptional regulator of the Notch pathway lies at the intersection of multiple signaling pathways that enhance the aggressiveness of cancer. The preclinical and clinical evidence supports the pro-oncogenic function of Notch signaling in various tumor subtypes. Owing to its oncogenic role, the Notch signaling pathway assists in enhanced tumorigenesis by facilitating angiogenesis, drug resistance, epithelial to mesenchymal transition, etc., which is also attributed to the poor outcome in patients. Therefore, it is extremely vital to discover a suitable inhibitor to downregulate the signal-transducing ability of Notch. The Notch inhibitory agents, such as receptor decoys, protease (ADAM and γ-secretase) inhibitors, and monoclonal/bispecific antibodies, are being investigated as candidate therapeutic agents. Studies conducted by our group exemplify the promising results in ablating tumorigenic aggressiveness by inhibiting the constituents of the Notch pathway. This review deals with the detailed mechanism of the Notch pathways and their implications in various malignancies. It also bestows us with the recent therapeutic advances concerning Notch signaling in the context of monotherapy and combination therapy.

We investigated a novel 4-phenoxy-quinoline-based scaffold that mislocalizes the essential mitotic kinase, Aurora kinase B (AURKB). Here, we evaluated the impact of halogen substitutions (F, Cl, Br, and I) on this scaffold with respect to various drug parameters. Br-substituted LXY18 was found to be a potent and orally bioavailable disruptor of cell division, at sub-nanomolar concentrations. LXY18 prevents cytokinesis by blocking AURKB relocalization in mitosis and exhibits broad-spectrum antimitotic activity in vitro. With a favorable pharmacokinetic profile, it shows widespread tissue distribution including the blood–brain barrier penetrance and effective accumulation in tumor tissues. More importantly, it markedly suppresses tumor growth. The novel mode of action of LXY18 may eliminate some drawbacks of direct catalytic inhibition of Aurora kinases. Successful development of LXY18 as a clinical candidate for cancer treatment could enable a new, less toxic means of antimitotic attack that avoids drug resistance mechanisms.

Dasatinib, a tyrosine kinase inhibitor, has been shown to produce anti-inflammatory activity and impair vascular integrity in vivo, including during skin wound healing, potentially promoting the repair process. Given that dasatinib is a lipophilic small molecule capable of penetrating skin, topical dasatinib might provide benefits in wound healing. In the present study, we investigated the impact of dasatinib ointments in skin wound healing in mice. A full thickness excisional skin wound (4 mm diameter) was generated on the shaved dorsum of eight-week-old C57BL/6 mice. Dasatinib ointment (0.1 or 0.2% w/w) or ointment base was applied twice daily (every 12 h) for 10 days. Elizabethan collars were used to prevent animal licking. The wound size was monitored daily for 14 days. The results showed that dasatinib ointments, particularly 0.1% dasatinib, promoted a 16–23% reduction in wound size (p < 0.05) during day 2 to day 6 postinjury compared to controls. Immunohistochemistry analyses demonstrated a reduction in wound neutrophils (38% reduction, p = 0.04), macrophages (47% reduction, p = 0.005), and tumor necrosis factor-α levels (73% reduction, p < 0.01), together with an induction of vascular leakage-mediated fibrin(ogen) accumulation (2.5-fold increase, p < 0.01) in the wound during day 3 postinjury (an early phase of repair) in 0.1% dasatinib-treated mice relative to control mice. The anti-inflammatory and vascular hyperpermeability activities of dasatinib were associated with an enhanced healing process, including increased keratinocyte proliferation (1.8-fold increase in Ki67+ cells, p < 0.05) and augmented angiogenesis (1.7-fold increase in CD31+ area, p < 0.05), compared to the ointment base-treated group. Following treatment with 0.2% dasatinib ointment, minor wound bleeding and scab reformation were observed during the late phase, which contributed to delayed healing. In conclusion, our data suggest that dasatinib ointment, mainly at 0.1%, promotes the repair process by reducing inflammation and producing a local and temporal vascular leakage, leading to an increase in fibrin(ogen) deposition, re-epithelialization, and angiogenesis. Therefore, topical dasatinib might be a potential novel candidate to facilitate skin wound healing.

This Viewpoint identifies some of the pitfalls in the bioavailability of water-soluble drugs and introduces a novel bias we term the “hypohydration bias”. We suggest that future bioavailability studies take some important neglected confounding factors into account, and we propose that, to avoid such a bias, some relevant variables such as serum and urine osmolality, dry weight adjustment, fluid balance, semi-nude body mass, saliva osmolality, saliva total protein concentration, and urine specific gravity should be controlled to increase the precision of the bioavailability measurements. We suggest that a new definition of hydration status is needed, and that systematic protocols of bioavailability studies should be revisited.

Mutations in connexin 26 (Cx26) cause hearing disorders of a varying degree. Herein, to identify compounds capable of restoring the function of mutated Cx26, a novel miniaturized microarray-based screening system was developed to perform an optical assay of Cx26 functionality. These molecules were identified through a viability assay using HeLa cells expressing wild-type (WT) Cx26, which exhibited sensitivity toward the HSP90 inhibitor radicicol in the submicromolar concentration range. Open Cx26 hemichannels are assumed to mediate the passage of molecules up to 1000 Da in size. Thus, by releasing radicicol, WT Cx26 active hemichannels in HeLa cells contribute to a higher survival rate and lower cell viability when Cx26 is mutated. HeLa cells expressing Cx26 mutations exhibited reduced viability in the presence of radicicol, such as the mutants F161S or R184P. Next, molecules exhibiting chemical chaperoning activity, suspected of restoring channel function, were assessed regarding whether they induced superior sensitivity toward radicicol and increased HeLa cell viability. Through a viability assay and microarray-based flux assay that uses Lucifer yellow in HeLa cells, compounds 3 and 8 were identified to restore mutant functionality. Furthermore, thermophoresis experiments revealed that only 3 (VRT-534) exhibited dose-responsive binding to recombinant WT Cx26 and mutant Cx26K188N with half maximal effective concentration values of 19 and ∼5 μM, respectively. The findings of this study reveal that repurposing compounds already being used to treat other diseases, such as cystic fibrosis, in combination with functional bioassays and binding tests can help identify novel potential candidates that can be used to treat hearing disorders.

Analogues of 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) are being sold on recreational drug markets and developed as potential medications for psychedelic-assisted therapies. Many of these tryptamine-based psilocybin analogues produce psychedelic-like effects in rodents and humans primarily by agonist activity at serotonin 2A receptors (5-HT2A). However, the comprehensive pharmacological target profiles for these compounds compared to psilocybin and its active metabolite 4-hydroxy-N,N-dimethyltryptamine (psilocin) are unknown. The present study determined the receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin across a broad range of potential targets. Specifically, we examined tryptamine psychedelics with different 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl (dimethyl, methyl-ethyl, diethyl, methyl-propyl, ethyl-propyl, diisopropyl, methyl-allyl, diallyl) substitutions. Further, the psilocybin analogue 4-propionoxy-N,N-dimethyltryptamine (4-PrO-DMT) was administered to mice in experiments measuring head twitch response (HTR), locomotor activity, and body temperature. Overall, the present pharmacological profile screening data show that the tryptamine psychedelics target multiple serotonin receptors, including serotonin 1A receptors (5-HT1A). 4-Acetoxy and 4-propionoxy analogues of 4-hydroxy compounds displayed somewhat weaker binding affinities but similar target profiles across 5-HT receptors and other identified targets. Additionally, differential binding screen profiles were observed with N,N-dialkyl position variations across several non-5-HT receptor targets (i.e., alpha receptors, dopamine receptors, histamine receptors, and serotonin transporters), which could impact in vivo pharmacological effects of the compounds. In mouse experiments, 4-PrO-DMT displayed dose-related psilocybin-like effects to produce 5-HT2A-mediated HTR (0.3–3 mg/kg s.c.) as well as 5-HT1A-mediated hypothermia and hypolocomotion (3–30 mg/kg s.c.). Lastly, our data support a growing body of evidence that the 5-HT2A-mediated HTR induced by tryptamine psychedelics is attenuated by 5-HT1A receptor agonist activity at high doses in mice.

Angiogenesis is a critical step in tumor growth, development, and invasion. Nascent tumor cells secrete vascular endothelial growth factor (VEGF) that significantly remodels the tumor microenvironment through interaction with multiple receptors on vascular endothelial cells, including type 2 VEGF receptor (VEGFR2). The complex pathways initiated by VEGF binding to VEGFR2 lead to enhanced proliferation, survival, and motility of vascular endothelial cells and formation of a new vascular network, enabling tumor growth. Antiangiogenic therapies that inhibit VEGF signaling pathways were among the first drugs that targeted stroma rather than tumor cells. Despite improvements in progression-free survival and higher response rates relative to chemotherapy in some types of solid tumors, the impact on overall survival (OS) has been limited, with the majority of tumors eventually relapsing due to resistance or activation of alternate angiogenic pathways. Here, we developed a molecularly detailed computational model of endothelial cell signaling and angiogenesis-driven tumor growth to investigate combination therapies targeting different nodes of the endothelial VEGF/VEGFR2 signaling pathway. Simulations predicted a strong threshold-like behavior in extracellular signal-regulated kinases 1/2 (ERK1/2) activation relative to phosphorylated VEGFR2 levels, as continuous inhibition of at least 95% of receptors was necessary to abrogate phosphorylated ERK1/2 (pERK1/2). Combinations with mitogen-activated protein kinase/ERK kinase (MEK) and spingosine-1-phosphate inhibitors were found to be effective in overcoming the ERK1/2 activation threshold and abolishing activation of the pathway. Modeling results also identified a mechanism of resistance whereby tumor cells could reduce pERK1/2 sensitivity to inhibitors of VEGFR2 by upregulation of Raf, MEK, and sphingosine kinase 1 (SphK1), thus highlighting the need for deeper investigation of the dynamics of the crosstalk between VEGFR2 and SphK1 pathways. Inhibition of VEGFR2 phosphorylation was found to be more effective at blocking protein kinase B, also known as AKT, activation; however, to effectively abolish AKT activation, simulations identified Axl autophosphorylation or the Src kinase domain as potent targets. Simulations also supported activating cluster of differentiation 47 (CD47) on endothelial cells as an effective combination partner with tyrosine kinase inhibitors to inhibit angiogenesis signaling and tumor growth. Virtual patient simulations supported the effectiveness of CD47 agonism in combination with inhibitors of VEGFR2 and SphK1 pathways. Overall, the rule-based system model developed here provides new insights, generates novel hypothesis, and makes predictions regarding combinations that may enhance the OS with currently approved antiangiogenic therapies.

Breast cancer is one of the major causes of death in women worldwide. It is a diverse illness with substantial intersubject heterogeneity, even among individuals with the same type of tumor, and customized therapy has become increasingly important in this sector. Because of the clinical and physical variability of different kinds of breast cancers, multiple staging and classification systems have been developed. As a result, these tumors exhibit a wide range of gene expression and prognostic indicators. To date, no comprehensive investigation of model training procedures on information from numerous cell line screenings has been conducted together with radiation data. We used human breast cancer cell lines and drug sensitivity information from Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases to scan for potential drugs using cell line data. The results are further validated through three machine learning approaches: Elastic Net, LASSO, and Ridge. Next, we selected top-ranked biomarkers based on their role in breast cancer and tested them further for their resistance to radiation using the data from the Cleveland database. We have identified six drugs named Palbociclib, Panobinostat, PD-0325901, PLX4720, Selumetinib, and Tanespimycin that significantly perform on breast cancer cell lines. Also, five biomarkers named TNFSF15, DCAF6, KDM6A, PHETA2, and IFNGR1 are sensitive to all six shortlisted drugs and show sensitivity to the radiations. The proposed biomarkers and drug sensitivity analysis are helpful in translational cancer studies and provide valuable insights for clinical trial design.

Triple-negative breast cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses. In certain cancers, AhR activation by select small molecules induces cell cycle arrest or apoptosis via activation of tumor-suppressive transcriptional programs. AhR is expressed in triple-negative breast cancers, presenting a tractable therapeutic opportunity. Here, we identify a novel ligand of the aryl hydrocarbon receptor that potently and selectively induces cell death in triple-negative breast cancer cells and TNBC stem cells via the AhR. Importantly, we found that this compound, Analog 523, exhibits minimal cytotoxicity against multiple normal human primary cells. Analog 523 represents a high-affinity AhR ligand with potential for future clinical translation as an anticancer agent.

In this paper, we review and analyze the commonly available wound healing models reported in the literature and discuss their advantages and issues, considering their relevance and translational potential to humans. Our analysis includes different in vitro and in silico as well as in vivo models and experimental techniques. We further explore the new technologies in the study of wound healing to provide an all encompassing review of the most efficient ways to proceed with wound healing experiments. We revealed that there is not one model of wound healing that is superior and can give translatable results to human research. Rather, there are many different models that have specific uses for studying certain processes or stages of wound healing. Our analysis suggests that when performing an experiment to assess stages of wound healing or different therapies to enhance healing, one must consider not only the species that will be used but also the type of model and how this can best replicate the physiology or pathophysiology in humans.

The use of adjuvant therapy is an attractive approach to manage sickle cell disease (SCD) symptomatically. The present study aimed to investigate the potential of ellagic acid as an adjuvant therapy with hydroxyurea (HU), a key drug for SCD with myelosuppressive toxic effects. A panel of experiments was performed using SCD patient’s blood (ex vivo) and transgenic mice model of SCD (in vivo). Ellagic acid exhibited the following beneficial pharmacological actions: (a) potent anti-sickling, polymerization inhibitory, and inherent non-hemolytic activity; (b) pronounced action to abrogate HU-induced neutropenia and to improve key hematological parameters during SCD (RBC, Hb, platelet levels); (c) considerable action to foster vascular tone (L-proline); (d) marked attenuating effect against oxidative stress (nitrotyrosine, hypoxanthine, MDA, GSH); (e) substantial inhibitory role against inflammation (analgesic activity and regulation of hemin, TNF-α, IL-1β, NF-κB/IκBα); (f) remarkable outcome of declining vaso-occlusive crisis (P-selectin, ERK1/2); (g) notable shielding deed against elevated biochemical marker for organ toxicity (creatinine); (h) noticeably prevented histopathological alterations of the spleen. Additionally, the pharmacokinetic study results of HU in the presence and absence of ellagic acid using a mouse model demonstrate that ellagic acid could be safely co-administered with HU. Overall findings suggest that ellagic acid is a promising candidate for adjuvant therapy in SCD based on its own significant ability against SCD and potentiating capability of HU action via targeting improvement at the various stages of pathophysiological complications during SCD and minimizing HU-induced toxicological manifestations.

Morphogenic signaling pathways govern embryonic development and tissue homeostasis on the cellular level. Precise control of such signaling events paves the way for innovative therapeutic approaches in the field of regenerative medicine. In line with these notions, bone morphogenic protein (BMP) is a major osteogenic driver and pharmacological stimulation of BMP signaling holds supreme potential for diseases and defects of the skeleton. Efforts to identify small-molecule modalities that activate or potentiate the BMP pathway have primarily been focused on the canonical signaling cascade. Here, we describe the phenotypic identification and development of specific carbazolomaleimides 2 as novel noncanonical BMP synergizers with submicromolar osteogenic cellular potency. The devised chemical tools are characterized to specifically regulate Id gene expression in a SMAD-independent, yet highly BMP-dependent fashion. Mechanistic studies revealed that GSK3 inhibition and increased β-catenin levels are partly responsible for this activity. The utility of the new BMP synergizer profile was further exemplified by showing how the synergistic action of canonical and noncanonical BMP enhancers additively amplifies BMP-dependent osteogenic outputs. Carbazolomaleimide 2b serves as a new and unique pharmacological tool for the modulation and study of the BMP pathway.