Biology subjects

Hwang, S.-Y.

Publications and source records attributed to Hwang, S.-Y..

5 recordsLinked to original sources

bioRxiv2026

Synthesis-aware generative design in trillion-scale chemical spaces for automated drug discovery

Autonomous drug discovery via generative molecular design is critically bottlenecked by the production of chemically intractable structures. Multi-trillion-scale make-on-demand libraries guarantee synthetic feasibility, but conventional virtual screening cannot efficiently navigate these vast spaces or address multi-parameter optimization. We introduce Hyper Screening X, a generative AI framework integrating structure-based design with automated synthesis hardware. By encoding deterministic reaction logic in a generative flow network, the framework evaluates only 10 million candidates to navigate an 11-trillion-compound space, jointly optimizing physicochemical properties while ensuring compatibility with automated synthesis. Prospective validation against an SLC1A5 variant with a cryptic interface yielded a 96% synthesis success rate and a 50% functional hit rate, identifying two first-in-class lead compounds. This synthesis-aware strategy advances autonomous, closed-loop drug discovery.

bioinformatics↗

bioRxiv2025

Leveraging BRG1 Driven Ferroptosis Resistance to Overcome Treatment Resistance

Resistance to Brutons tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. Here, we identify ferroptosis suppression as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL). Aberrant BRG1 activity protects cells from BTKi-induced ferroptosis by restricting reactive oxygen species (ROS) and labile iron. Mechanistically, BRG1 promotes resistance through both BTK-dependent survival signaling and a BTK-independent transcriptional program. The latter is mediated by BRG1-driven induction of MEF2B, which upregulates NDUFA4L2 to inhibit mitochondrial respiration, thereby blocking mitochondria-dependent ferroptosis. Pharmacologic inhibition of BRG1 disrupts these programs, restoring ferroptotic sensitivity and synergizing with BTKi across resistant MCL models. Together, these findings establish BRG1 as a central regulator of therapy resistance and provide a rationale for co-targeting BRG1 and BTK as a therapeutic strategy for B-cell malignancies.

cancer biology↗

bioRxiv2024

Synthesis and Biological Assessment of Chalcone and Pyrazoline Derivatives as novel inhibitor for ELF3-MED23 Interaction

HER2 overexpression significantly contributes to the aggressive nature and recurrent patterns observed in various solid tumors, notably gastric cancers. Trastuzumab, HER2-targeting monoclonal antibody drug, has shown considerable clinical success, however, readily emerging drug resistance emphasizes the pressing need for improved interventions in HER2-overexpressing cancers. To address this, we proposed targeting the protein-protein interaction (PPI) between ELF3 and MED23 as an alternative therapeutic approach to trastuzumab. In this study, we synthesized a total of 26 compounds consisting of 10 chalcones, 7 pyrazoline acetyl, and 9 pyrazoline propionyl derivatives, and evaluated their biological activity as potential ELF3-MED23 PPI inhibitors. Upon systematic analysis, candidate compound 10 was selected due to its potency in downregulating reporter gene activity of ERBB2 promoter confirmed by SEAP activity and its effect on HER2 protein and mRNA levels. Compound 10 effectively disrupted the binding interface between the ELF3 TAD domain and the 391-582 amino acid region of MED23, resulting in successful inhibition of the ELF3-MED23 PPI. This intervention led to a substantial reduction in HER2 levels and its downstream signals in the HER2-positive gastric cancer cell line. Subsequently, compound 10 induced significant apoptosis and anti-proliferative effects, demonstrating superior in vitro and in vivo anticancer activity overall. We found that the anticancer activity of compound 10 was not only restricted to trastuzumab-sensitive cases, but was also valid for trastuzumab-refractory clones. This suggests its potential as a viable therapeutic option for trastuzumab-resistant gastric cancers. In summary, compound 10 could be a novel alternative therapeutic strategy for HER2-overexpressing cancers, overcoming the limitations of trastuzumab.

pharmacology and toxicology↗

bioRxiv2023

Enhanced Omicron subvariant cross-neutralization efficacy of a monovalent SARS-CoV-2 BA.4/5 mRNA vaccine encoding a noncleaved, nonfusogenic spike antigen

The rapid emergence of diverse SARS-CoV-2 variants, notably the Omicron variant, poses challenges to vaccine development. Here, we present a noncleaved, nonfusogenic spike (S) protein eliciting robust B- and T-cell immune responses against Omicron BA.5. The antigen incorporates the R685S and R815A mutations, effectively preventing the shedding of the S1 subunit and eliminating fusogenic activity of the resulting S antigen, termed S(SA). Through reverse genetic analysis, we found that the noncleaved form S protein with the R685S mutation enhances ACE2-dependent viral entry in vitro compared to the wild-type S protein, without increasing the virulence of the mutant virus in mice. The mRNA vaccine encoding the Omicron BA.4/5 S(SA) antigen conferred protective immunity in mice following two doses of 1 g {Psi}-UTP- or UTP-incorporated mRNA vaccines. Despite a roughly 6-fold reduction in neutralizing potency, both mRNA vaccines exhibited broad neutralizing efficacy against Omicron subvariants, including the XBB lineage variants XBB.1.5 and XBB.1.16.

immunology↗

bioRxiv2017

Single-cell analysis of early antiviral gene expression reveals a determinant of stochastic IFNB1 expression

RIG-I-like receptors (RLRs) are cytoplasmic sensors of viral RNA that trigger the signaling cascade that leads to type I interferon (IFN) production. Transcriptional induction of RLRs by IFN is believed to play the role of positive feedback to further amplify viral sensing. We found that RLRs and several other IFN-stimulated genes (ISGs) are induced early in viral infection independent of IFN. Expression of these early ISGs requires IRF3/IRF7 and is highly correlated amongst them. Simultaneous detection of mRNA of IFNB1, viral replicase, and ISGs revealed distinct populations of IFNB1 expressing and non-expressing cells which are highly correlated with the levels of early ISGs but are uncorrelated with IFN-dependent ISGs and viral gene expression. Individual expression of RLRs made IFNB1 expression more robust and earlier, suggesting a causal relation between levels of RLR and induction of IFN.

biophysics↗