Dong-A ST (South Korea)

BackgroundDA‐7503 is a potential first‐in‐class, orally available small‐molecule inhibitor of tau oligomerization, currently in clinical development for the treatment of Alzheimer’s disease and primary tauopathies. The neurobehavioral and biochemical findings from AD and tauopathy mouse models revealed that DA‐7503 improved memory and recognition, and reduced tau aggregation and hyperphosphorylation in the brain. This study aimed to elucidate the pharmacological properties of DA‐7503, focusing on its potency and specificity for pathological tau isoforms, as well as its therapeutic effects on motor impairments and tau aggregation in the JNPL3 mouse model.MethodThe inhibitory potency of DA‐7503 on aggregation of 4R and 3R tau isoforms was evaluated in tau‐BiFC HEK293 cells. For in vivo studies, JNPL3 transgenic mice, expressing human P301L‐mutant tau, were administrated with DA‐7503 orally once daily for 4.5 months from 8 months of age. Therapeutic effects were assessed through motor impairment evaluations and analysis of pathological tau aggregation. Non‐clinical toxicity and safety pharmacology studies, including 28‐day rat and dog toxicity assessments, were conducted according to GLP principles.ResultThis study reports the non‐clinical characteristics of DA‐7503, a novel tau aggregation inhibitor, in terms of efficacy and safety. DA‐7503 demonstrated comparable inhibitory potency against aggregation of both 4R tau and 3R tau under various tau aggregation‐inducing conditions in tau‐BiFC cells. In JNPL3 mice, DA‐7503 treatment significantly improved motor function in several behavioral tests, including the open field, coat hanger, vertical grid, rotarod, and gait pattern analysis. Notably, a dose of 15 mg/kg was sufficient to reduce pathological tau aggregates in the brainstem and spinal cord of JNPL3 mice. Non‐clinical toxicity studies revealed that DA‐7503 has a favorable safety profile, supporting its clinical development.ConclusionOur findings suggest that DA‐7503, a novel tau aggregation inhibitor with great potencies against pathological 3R and 4R tau isoforms and a favorable non‐clinical safety profile, effectively restored motor function and reduced tau aggregates in the JNPL3 mouse model of tauopathy. These results highlight DA‐7503’s potential as a promising therapeutic candidate for Alzheimer’s disease and primary tauopathies, including frontotemporal dementia, progressive supranuclear palsy and corticobasal degeneration. DA‐7503 is currently undergoing a phase 1 clinical study.

Abstract Epidermal growth factor receptor (EGFR) mutations, including the L858R activating mutation in exon 21, are major drivers of non-small cell lung cancer (NSCLC) and are targeted by EGFR tyrosine kinase inhibitors (TKIs). However, despite significant initial clinical benefits, resistance to EGFR TKIs frequently develops due to secondary mutations such as T790M and C797S, which reduce the therapeutic efficacy of second- and third-generation inhibitors. Consequently, extensive efforts have been made to develop new small molecule inhibitors to overcome this resistance, including novel approaches such as proteolysis targeting chimera (PROTAC) technology. We identified a promising heterobifunctional degrader, SC2073, designed to target a unique allosteric binding site on mutant EGFR while sparing wild-type EGFR. SC2073 effectively induced the degradation of EGFR proteins harboring single, dual, or triple mutations through the ubiquitin-proteasome system. It exhibited potent anti-proliferative activity against Ba/F3 cells with common EGFR resistance mutations, including L858R, L858R/T790M, L858R/C797S, and L858R/T790M/C797S as well as NCI-H1975 (L858R/T790M) cells without affecting the expression levels of GSPT1 and SALL4, which are substrates of the E3 ligase protein (CRBN). Notably, SC2073 showed no effect on the proliferation of Ba/F3 and A549 cells expressing wild-type EGFR, thereby minimizing potential toxic side effects associated with wild-type EGFR inhibition. SC2073 demonstrated a favorable pharmacokinetic profile, rapidly degrading mutant EGFR in tumors within 6 hours of oral administration and maintaining efficacy for 24 hours. Further investigations confirmed that oral administration of SC2073 resulted in a dose-dependent, robust anti-tumor activity in allograft and xenograft models resistant to EGFR TKIs by promoting the degradation of mutant EGFR. In this study, we present SC2073, an orally bioavailable, highly potent, and mutant-selective degrader with the potential to provide more durable, safer, and improved therapeutic responses. SC2073 effectively inhibited the proliferation of Ba/F3 cell expressing EGFR mutants while sparing WT EGFR cells and it demonstrated robust anti-tumor activity in EGFR mutation-driven in vivo tumor models. Our data suggests that SC2073 could be a promising treatment option for NSCLC patients harboring various EGFR mutations, including L858R, T790M, and C797S, which are associated with acquired resistance to EGFR inhibitors. Citation Format: Jihoon Choi, Jun Gyu Kim, Ok Young Lee, Young Jun Park, Young Min Jeong, Chung Sil Lee, Sun Ho Choi, Hye Yeon Lee, Yu Jin Lee, Punna Reddy Ullapu, Dae Young Lee, Hye Sun Lee, Jong Ryoul Choi, Daseul Yoon, Yanghun Tae, Ji-Young An, Hyo Ju Lee, Bong Tae Kim, Mi-Kyung Kim. Discovery of SC2073, a potent and mutant selective EGFR degrader that overcomes 3rd generation EGFR inhibitors resistance in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5513.

Abstract Introduction: Src homology 2 domain-containing phosphatase 1 (SHP1) is a cytoplasmic protein tyrosine phosphatase (PTP) that is primarily expressed in hematopoietic cells and is commonly recognized as a negative regulator of multiple signaling pathways1. Previously, we showed that inhibition of the phosphatase activity of SHP1 by a novel SHP1 allosteric inhibitor, SB6299, results in the activation of innate and adaptive immune cells and enhanced anti-tumor immune responses2. Here, we report SB8091, an advanced SHP1 allosteric inhibitor with a promising initial safety profile and improved pharmacokinetic properties. Methods: SHP1 inhibitors were developed through a structure-based drug design approach, and optimized for cellular activity on target, in vitro ADME, and in vivo pharmacokinetic properties. Pharmacokinetic (PK) and preliminary toxicity studies were performed with mice. The lead series was assessed in in-vitro studies with mouse or human primary immune cells. In-vivo efficacy and pharmacodynamic data were generated using mouse syngeneic tumor models. Results: Structurally, SB8091 seemed to stabilize the autoinhibitory form of SHP1 as an allosteric inhibitor, in a nanomolar range and which can explain the outstanding selectivity compared to other PTP enzymes, including SHP2. In several human primary immune cell types, SB8091 significantly increased cytokine responses and demonstrated significantly enhanced activity in NK cells and macrophages against various cancer target cells. As a single agent, this compound exhibited inhibitory effects on tumor growth when administered orally, and the efficacy was further enhanced when co-administered with anti-PD1 antibodies in various syngeneic tumor models. Notably, this effect was associated with a pharmacodynamic response marked by increased levels of phosphorylated substrates regulated by SHP1. SB8091 exhibited favorable pharmacokinetic properties for oral administration, and SafetyScreen data showed a very low potential for off-target activity and drug-drug interactions. Additionally, during a 2-week repeat pilot toxicity study in mice, SB8091 demonstrated excellent tolerability even at high doses, indicating a high therapeutic index (TI > 100). Conclusion: Our advanced compound, SB8091, is a potent, highly selective, and orally bioavailable allosteric inhibitor of SHP1. It has demonstrated excellent efficacy as a monotherapy or in combination with immune checkpoint blockers, with favorable drug properties and safety profiles. Research to advance to the clinical stage is being conducted.

In this study, supercritical fluid-assisted spray-drying (SA-SD) was applied to achieve the micronization of fenofibrate particles possessing surface-active additives, such as d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sucrose mono palmitate (Sucroester 15), and polyoxyethylene 52 stearate (Myrj 52), to improve the pharmacokinetic and pharmacodynamic properties of fenofibrate. For comparison, the same formulation was prepared using a spray-drying (SD) process, and then both methods were compared. The SA-SD process resulted in a significantly smaller mean particle size (approximately 2 μm) compared to that of unprocessed fenofibrate (approximately 20 μm) and SD-processed particles (approximately 40 μm). There was no significant difference in the effect on the particle size reduction among the selected surface-active additives. The microcomposite particles prepared with surface-active additives using SA-SD exhibited remarkable enhancement in their dissolution rate due to the synergistic effect of comparably moderate wettability improvement and significant particle size reduction. In contrast, the SD samples with the surface-active additives exhibited a decrease in dissolution rate compared to that of the unprocessed fenofibrate due to the absence of particle size reduction, although wettability was greatly improved. The results of zeta potential and XPS analyses indicated that the surface-active additive coverage on the surface layer of the SD-processed particles with a better wettability was higher than that of the SA-SD-processed composite particles. Additionally, after rapid depletion of hydrophilic additives that were excessively distributed on the surfaces of SD-processed particles, the creation of a surface layer rich in poorly water-soluble fenofibrate resulted in a decrease in the dissolution rate. In contrast, the surface-active molecules were dispersed homogeneously throughout the particle matrix in the SA-SD-processed microparticles. Furthermore, improved pharmacokinetic and pharmacodynamic characteristics were observed for the SA-SD-processed fenofibrate microparticles compared to those for the SD-processed fenofibrate particles. Therefore, the SA-SD process incorporating surface-active additives can efficiently micronize poorly water-soluble drugs and optimize their physicochemical and biopharmaceutical characteristics.

DA-9601 is an extract obtained from Artemisia asiatica, which has been reported to have anti-inflammatory effects on gastrointestinal lesions; however, its possible anti-inflammatory effects on the small intestine have not been studied yet. Therefore, in this study, we investigated the protective effects of DA-9601 against the ACF-induced small intestinal inflammation. Inflammation of the small intestine was confirmed by histological studies and the changes in the CD4+ T cell fraction induced by the inflammation-related cytokines, and the inflammatory reactions were analyzed. Multifocal discrete small necrotic ulcers with intervening normal mucosa were frequently observed after treatment with ACF. The expression of IL-6, IL-17, and TNF-α genes was increased in the ACF group; however, it was found to have been significantly decreased in the DA-9601 treated group. In addition, DA-9601 significantly decreased the levels of proinflammatory mediators such as IL-1β, GM-CSF, IFN-γ, and TNF-α; the anti-inflammatory cytokine IL-10, on the other hand, was observed to have increased. It is known that inflammatory mediators related to T cell imbalance and dysfunction continuously activate the inflammatory response, causing chronic tissue damage. The fractions of IFN-γ+ Th1 cells, IL-4+ Th2 cells, IL-9+ Th9 cells, IL-17+ Th17 cells, and Foxp3+ Treg cells were significantly decreased upon DA-9601 treatment. These data suggest that the inflammatory response induced by ACF is reduced by DA-9601 via lowering of the expression of genes encoding the inflammatory cytokines and the concentration of inflammatory mediators. Furthermore, DA-9601 inhibited the acute inflammatory response mediated by T cells, resulting in an improvement in ACF-induced enteritis.

The aim of this study was to investigate the effects of various parameters at each control strategy in drug product degradation on the stability of pemetrexed in injectable aqueous solution. A forced degradation study confirmed that oxidation is the main mechanism responsible for the degradation of pemetrexed in aqueous solutions. As control strategies, the antioxidant levels, drug concentration, pH of the control formulation, dissolved oxygen (DO) levels in the control process, and headspace oxygen levels in the control packaging were varied, and their effects on the stability of pemetrexed were evaluated. Sodium sulfite was found to be particularly effective in preventing the color change, and N-acetylcysteine (NAC) had a significant effect in preventing chemical degradation. The sulfite and NAC were found to stabilize pemetrexed in the aqueous solution by acting as sacrificial reductants. A pH below 6 caused significant degradation. The stability of pemetrexed in the solution increased as the concentration of the drug increased from 12.5 to 50 mg/mL. In addition, the DO levels in the solution were controlled by nitrogen purging, and the oxygen levels in headspace were controlled by nitrogen headspace, which also had significant positive effects in improving the stability of the pemetrexed solution; thus, it was confirmed that molecular oxygen is involved in the rate-limiting oxidation step. Based on these results obtained by observing the effects of various control strategies, the optimal formulation of an injectable solution of pemetrexed is suggested as follows: sodium sulfite at 0.06 mg/mL, as an antioxidant for prevention of color change; NAC at 1.63 mg/mL, as an antioxidant for prevention of chemical degradation; pH range 7–8; DO levels below 1 ppm; and headspace oxygen levels below 1%. In conclusion, it can be suggested that this study, which includes well-designed control strategies, can lead to a better understanding of the complex degradation mechanism of pemetrexed; thus, it can lead to the development of an injectable solution formulation of pemetrexed, with improved stability.

Udenafil is a phosphodiesterase-5 inhibitor used to treat erectile dysfunction. Although udenafil is not predominantly eliminated by the kidney, renal impairment can alter its secretion/transport pathways. Drug pharmacokinetics and safety must therefore be assessed in subjects with a renal impairment. We investigated the effects of impaired renal function on the pharmacokinetics and safety of a single 100-mg oral dose of udenafil in a single-dose, open-label, parallel-group study of 31 subjects. Cockcroft-Gault creatinine clearance was used to stratify these subjects into healthy controls (>80 mL·min-1 ) and individuals with mild (50 to ≤80 mL·min-1 ), moderate (30 to ≤50 mL·min-1 ), and severe (<30 mL·min-1 ) renal impairment. Pharmacokinetic measurements and safety assessments indicated that the geometric mean of the area under the concentration-time curve to the last measurement in mildly, moderately, and severely renally impaired subjects was 1.30- (90% CI 1.05-1.60), 1.62- (90% CI 1.28-2.06), and 1.60- (90% CI 1.28-2.01) fold higher, respectively, than the healthy controls. The geometric mean of the maximum observed concentration was 1.41- (90% CI 1.05-1.88), 2.02- (90% CI 1.47-2.79), and 1.65- (90% CI: 1.21-2.24) fold higher, respectively. Significant correlations were observed among the creatinine clearance, oral clearance, and maximum concentration of udenafil (P < .01). All adverse events were mild, and no subject discontinued the study. Udenafil administration was well tolerated in all groups. In view of the clinical relevance of drug exposure, our findings indicate that a dose adjustment of udenafil is warranted in subjects with moderate or severe renal impairment.

Detecting genetic interactions associated with complex disease is a major issue in genetic studies. Although a number of methods to detect gene-gene interactions for population-based Genome-Wide Association Studies (GWAS) have been developed, the statistical methods for family-based GWAS have been limited. In this study, we propose a new Bayesian approach called MB-TDT to find high-order genetic interactions for pedigree data. The MB-TDT method combines the Markov blanket algorithm with classical Transmission Disequilibrium Test (TDT) statistic. The Incremental Association Markov Blanket (IAMB) algorithm was adopted for large-scale Markov blanket discovery. We evaluated the proposed method using both real and simulated data sets. In a simulation study, we compared the power of MB-TDT with conditional logistic regression, Multifactor Dimensionality Reduction (MDR) and MDR-pedigree disequilibrium test (MDR-PDT). We demonstrated the superior power of MB-TDT in many cases. To demonstrate the approach, we analysed the Korean autism disorder GWAS data. The MB-TDT method can identify a minimal set of causal SNPs associated with a specific disease, thus avoiding an exhaustive search.

In recent years, detecting interactions between different genes has become a hot topic, for better understanding multigenic, complex diseases. For population-based genome-wide association studies (GWAS), a number of methods to detect gene-gene interactions such as logistic regression, multifactor dimensionality reduction (MDR) and support vector machine (SVM), have been applied. Bayesian approaches such as BEAM (Bayesian marker partition model) and DASSO-MB (detection of association using Markov Blanket) have also been suggested. However, the studies for family-based GWAS have been limited. In this study, we developed a new Markov Blanket-based algorithm called MB-TDT to find gene-gene interactions for pedigree data. A transmission disequilibrium test statistic was used as an association measure and the incremental association a Markov Blanket (IAMB) algorithm was applied to find Markov Blanket. This proposed MB-TDT method can identify a minimal set of causal SNPs, associated with a specific disease, thus avoiding an exhaustive search. By conducting a simulation study to compare MB-TDT with current methods, we show its superior high power in many cases, and lower false positive rates, in others.

Nerve growth factor (NGF)-induced neuronal regeneration has emerged as a strategy to treat neuronal degeneration-associated disorders. However, direct NGF administration is limited by the occurrence of adverse effects at high doses of NGF. Therefore, development of a therapeutic strategy to promote the NGF trophic effect is required. In view of the lack of understanding of the mechanism for potentiating the NGF effect, this study investigated molecular targets of DA-9801, a well-standardized Dioscorea rhizome extract, which has a promoting effect on NGF. An increase in intracellular calcium ion level was induced by DA-9801, and chelation of extracellular calcium ions with ethylene-bis(oxyethylenenitrilo)tetraacetic acid (EGTA) suppressed the potentiating effect of DA-9801 on NGF-induced neurite outgrowth. In addition, EGTA treatment reduced the DA-9801-induced phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), the major mediators of neurite outgrowth. To find which calcium ion-permeable channel contributes to the calcium ion influx induced by DA-9801, we treated PC12 cells with various inhibitors of calcium ion-permeable channels. NF449, a P2X1 receptor selective antagonist, significantly abolished the potentiating effect of DA-9801 on NGF-induced neurite outgrowth and abrogated the DA-9801-induced ERK1/2 phosphorylation. In addition, transfection with siRNA of P2X1 receptor significantly reduced the DA-9801-enhanced neurite outgrowth. In conclusion, calcium ion influx through P2X1 receptor mediated the promoting effect of DA-9801 on NGF-induced neurite outgrowth via ERK1/2 phosphorylation.