Information about Dr. Xue’s current research projects can be found on this webpage.
Project 1: Small-molecule therapeutics enhance chemotherapy efficacy by co-activating Nrf2 and hCAR pathways
Doxorubicin (DOX) and cyclophosphamide (CPA) are cornerstone chemotherapies for cancers such as triple-negative breast cancer (TNBC), Non-Hodgkin’s lymphoma, and various leukemias. While initially effective, these regimens often fail due to off-target toxicities, particularly dose-related CPA toxicity and DOX-induced cardiotoxicity, which limits dosing and reduces overall efficacy. DOX cardiotoxicity is linked to disruption of the Nrf2-antioxidant pathway, while CPA requires metabolic activation by CYP2B6, a cytochrome P450 enzyme regulated by the human constitutive androstane receptor (hCAR). To improve DOX/CPA therapy, we aimed to develop compounds that both protect Nrf2 signaling and enhance hCAR-CYP2B6 activity. Through high-throughput screening, computational modeling, and medicinal chemistry, we developed a novel class of dual Nrf2/hCAR activators, including leads CN06 and YA9073. These dual activators significantly reduced DOX-induced cardiotoxicity in a human co-culture model of hepatocytes, TNBC cells, and cardiomyocytes, while simultaneously boosting CPA activation and enhancing anti-cancer efficacy in TNBC cells.
Recent Publications:
Liang D, Li L, Ai Y, Li Z, Hedrich WD, Sakauru S, Lynch C, Yu W, Watts-Ouattara I, Heyward S, Xia M, MacKerell, Jr. AD, Wang H, Xue F. 2025. A Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies. J. Med. Chem. 68(7):7044-7061. PMID: 40145447.
Stern S, Liang D, Li L, Kurian R, Lynch C, Srilatha S, Heyward S, Zhang J, Kareen KA, Chun Y W, Huang R, Xia M, Charles C, Xue F, Wang H. 2022. Targeting CAR-Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment. JCI Insight 7(12):e153868. PMID: 35579950.
Liang D, Li L, Lynch C, Mackowiak B, Hedrich WD, Ai Y, Yin Y, Heyward S, Xia M, Wang H, Xue F. 2019. Human constitutive androstane receptor agonist DL5016: a novel sensitizer for cyclophosphamide-based chemotherapies. Eur. J. Med. Chem. 179:84-99. PMID: 31247375.
Liang D, Li L, Lynch C, Xia M, Wang H, Xue F. 2019. DL5050: a selective agonist for the human constitutive androstane receptor. ACS Med. Chem. Lett. 10(7):1039-1044. PMID: 31312405.
Fundings: R01 CA295603 (2025-30, pending), MII (2018-19)
Project 2: Gallium complexes as anti-pseudomonal agents by targeting the bacterial extracellular hemophore HasAp
Pseudomonas aeruginosa (Pa), an ESKAPE pathogen, is difficult to treat due to antibiotic resistance and biofilm formation. Iron is essential for its virulence, acquired via siderophores, the Feo system, and heme uptake pathways (Has and Phu). In CF patients, Pa shifts from siderophore use to increased heme uptake. In infection models, hasAp and hasR were highly upregulated, and a ΔhasR mutant showed reduced growth and virulence, highlighting the has system as a therapeutic target. Gallium (Ga³⁺), a redox-inactive Fe³⁺ mimic, shows anti-Pa activity, but Ga(NO₃)₃ (Ganite) induces iron starvation, triggering siderophore and virulence factor overproduction. In 2024, we patented GaSal-2, a water-soluble compound that binds HasAp, blocks has transcription, inhibits Pa growth, and disrupts biofilms without host toxicity. Building on this, we developed KJ3001, a lead compound with greater potency against has system activation.
Recent Publications:
Frank A, Hwang L, Witt W, Centola G, Johnson K, Ai Y, Sen-Kilic E, Pyles GM, Huckaby AB, Blackwood, CB, Miller SJ, Hudson SM, Kerr A, Imler GH, Hom K, MacKerell Jr. AD, Barbier M, Wilks A, Xue F. 2025. GaSal-2: A Water-Soluble Antipseudomonal Agent Targeting the Extracellular Hemophore HasAp. ACS Infect. Dis. Under revision.
Krug SA, Frank A, Hwang L, Worth M, Johnson K, Rojas C, Muller L, Michel SLJ, Wilks A, Xue F, Kane MA. 2025, Application of Pre-Clinical ADME in Vitro Techniques for the Characterization and Compound Library Optimization of Novel Antibiotic Gallium Salophen (GaSal). Drug Metabolism and Disposition, 100080.
Centola G, Deredge DJ, Hom K, Dent AT, Wilks A, Xue F. 2020. Gallium (III) salophen as a dual inhibitor of Pseudomonas aeruginosa heme sensing and iron acquisition. ACS Infect. Dis. 6(8): 2073-2085. PMID: 32551497.
Fundings: UM-BILD (2025-26), R21 AI161313 (2021-24), MII (2020-21)
Project 3: Therapeutics targeting the Wnt/β-catenin signaling pathway
Dysregulation of the Wnt/β-catenin pathway is a key contributor to metabolic diseases such as liver and renal fibrosis, metabolic dysfunction-associated steatohepatitis (MASH), and colorectal cancer (CRC). In 2019, we identified novel Axin-stabilizing compounds, including YW1128 and YW2065, which inhibit Wnt signaling and activate AMPK. Lead compound YW2065 selectively targets Wnt-dependent CRC cells and shows strong anti-tumor efficacy in vitro and in vivo. Based on this scaffold, we developed YA6060, a next-generation compound that retains dual Wnt inhibition and AMPK activation while demonstrating a favorable drug-like profile. Proteomic analysis using biotinylated analogs identified TAB182 (tankyrase-binding protein 1) as the molecular target of these compounds. YA6060 shows promising efficacy in mouse models of MASH, CRC, and renal fibrosis, with excellent oral bioavailability (F = 75%), long half-life (t₁/₂ = 160 min), high maximum tolerated dose (MTD >500 mg/kg), and high aqueous solubility (>75 mg/mL), supporting its potential as a therapeutic Axin stabilizer.
Recent Publications:
Ai Y, Sakamuru S, Imler G, Xia M, Xue F. 2022. Wnt/β-catenin signaling inhibitors with improved aqueous solubility and anti-leukemia activity by disrupting molecular planarity. Bioorg. Med. Chem. 69:116890. PMID: 35777269.
Yang W, Li Y, Ai Y, Obianom ON, Guo D, Yang H, Sakamuru S, Xia M, Shu Y, Xue F. 2019. “Pyrazole-4-carboxamide (YW2065): A therapeutic candidate for colorectal cancer via dual activities of Wnt/β-catenin signaling inhibition and AMP-activated protein kinase (AMPK) activation” J. Med. Chem. 62(24):11151-11164. PMID: 31769984.
Obianom ON, Ai Y, Li Y, Yang W, Guo D, Yang H, Sakamuru S, Xia M, Xue F, Shu Y. 2019. Triazole-based inhibitors of the Wnt/β-catenin signaling pathway improves glucose and lipid metabolism in diet-induced obese mice. J. Med. Chem. 62(2):724-741. PMID: 30605343.
Fundings: UM-BILD (2024-25), R01 DK133421 (2023-28), MII (2021-22), MII (2018-19), UM-Venture (2016-17)
Project 4: ALDH2 inhibitors for the treatment of alcohol use disorder (AUD)
AUD is a major public health concern. Disulfiram (DSF, Antabuse), an FDA-approved aversion therapy, works by inhibiting aldehyde dehydrogenase 2 (ALDH2), leading to acetaldehyde buildup and aversive symptoms (e.g., flushing, nausea, headache) upon alcohol intake. DSF is rapidly converted to diethyldithiocarbamate (DDTC), which is then methylated and oxidized in the liver to MeDDTC-SO, an irreversible ALDH2 inhibitor. However, DSF’s use is limited by serious side effects: respiratory issues, cardiac complications, and seizures. These arise in part because DDTC and its unstable byproducts (diethylamine and toxic CS₂) circulate systemically. DDTC also forms cytotoxic metal chelates with Cu²⁺ and Zn²⁺, inhibiting essential metalloenzymes. To address this, we developed YA8136, a liver-specific prodrug of DDTC activated only by hepatocyte enzymes CES1 and cytochrome P450. In preliminary studies, YA8136 showed a favorable safety profile, supporting its potential as a first-in-class liver-targeted ALDH2 inhibitor for AUD. In parallel, we synthesized MeDDTC-SO mimetics that covalently inhibit ALDH2 with strong potency and isozyme selectivity, offering an additional therapeutic avenue.
Fundings: R21 AA030336 (2023-26)