Research Terms
Computer Programming Information Science Biochemistry Biophysics Medicinal Chemistry Pharmacology Natural Sciences Chemistry Crystallography Thermodynamics Chaos
Keywords
Biochemistry Cell Biology Computational Biology Computational Chemistry Computer-Aided Drug Design Drug Design Drug Discovery Free Energy Simulation Inflammation Molecular Biophysics Neuroinflammation Organic Chemistry Physical Chemistry Protein Crystallography Structural Biology Structure-Based Drug Design Targeted Cancer Drug Design
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Prof. Chenglong Li obtained his B. Sc. and M. Sc. in Chemistry and Physical Chemistry from Beijing University, respectively; and Ph. D. in Biophysics from Cornell University. In general, his lab focuses on molecular recognition, with a strong application to structure-based computer-aided drug design. It combines molecular simulation, AI/deep learning, synthetic chemistry, X-ray protein crystallography, thermodynamic measurements, cellular techniques and in vivo animal models (in collaboration) to explore molecular interactions, especially protein-ligand interactions, at molecular, cellular and organismal levels. The ongoing projects include both computational method development and drug design applications, for example: 1) pioneering development of a novel Multiple Ligand Simultaneous Docking (MLSD) strategy, with great potential for Fragment-Based Drug Design (FBDD); 2) developing start-of-the-art deep-learning-based protein/ligand binding models and ensuing AI-based drug optimization design platform; 3) design and discovery of drugs targeting the IL-6/STAT3 inflammatory and oncogenic pathway for targeted therapy; 4) design and discovery of drugs targeting the PRMT5 inflammatory and oncogenic pathway for targeted therapy; 5) design and discovery of drugs targeting the Hippo YAP/TEAD signaling pathway. It is exciting that several designed compounds can be realistically optimized for potential novel cancer therapy, alone or in combination with other means.
American Association for Cancer Research, Member; 2007 - present
American Crystallographic Assocaition, Member; 1995 - present
American Chemical Society, Member; 1991 - present
DDNS (Drug Discovery for the Nervous System), NIH (National Institutes of Health); 2016 - 2019
Prof. Chenglong Li obtained his B. Sc. and M. Sc. in Chemistry and Physical Chemistry from Beijing University, respectively; and Ph. D. in Biophysics from Cornell University. In general, his lab focuses on molecular recognition, with a strong application to structure-based computer-aided drug design. It combines molecular simulation, AI/deep learning, synthetic chemistry, X-ray protein crystallography, thermodynamic measurements, cellular techniques and in vivo animal models (in collaboration) to explore molecular interactions, especially protein-ligand interactions, at molecular, cellular and organismal levels. The ongoing projects include both computational method development and drug design applications, for example: 1) pioneering development of a novel Multiple Ligand Simultaneous Docking (MLSD) strategy, with great potential for Fragment-Based Drug Design (FBDD); 2) developing start-of-the-art deep-learning-based protein/ligand binding models and ensuing AI-based drug optimization design platform; 3) design and discovery of drugs targeting the IL-6/STAT3 inflammatory and oncogenic pathway for targeted therapy; 4) design and discovery of drugs targeting the PRMT5 inflammatory and oncogenic pathway for targeted therapy; 5) design and discovery of drugs targeting the Hippo YAP/TEAD signaling pathway. It is exciting that several designed compounds can be realistically optimized for potential novel cancer therapy, alone or in combination with other means.
Speaker Topics
Ai Drug Design Ai-based Drug Design Computer-Aided Drug Design Drug Design Structure-Based Drug Design
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These small molecule inhibitors target TEA domain (TEAD) proteins, with the potential to treat diseases with altered Hippo signaling, such as Hepatocellular Carcinoma (HCC) and Hepatoblastoma (HB). The Hippo signaling pathway is vital to organ growth control, stem cell function, regeneration, and tumor suppression. Inactivation of the Hippo pathway leads to the dephosphorylation of YAP/TAZ proteins and their translocation to the nucleus, where they interact with TEAD transcription factors, activating the transcription and translation of genes involved in cell proliferation and survival, as well as leading to carcinogenesis. A broad range of carcinomas, including HCC, present a high rate of dysregulation of the Hippo pathway. For this reason, targeting the YAP-TEAD complex, essential for regulating the Hippo pathway, is an attractive strategy for treating these cancers.
HCC is one of the most common malignant cancers, with increasing incidence and mortality in recent years in the United States. The disease progression in patients involves severe liver inflammation and fibrosis that correlate with the deregulation of various signaling pathways and genetic aberrations. Patients with advanced HCC have a poor prognosis. Although there are several systemic therapies for the treatment of HCC, drug resistance, and undesired toxicities remain a hurdle. Only 12 percent of patients have a one-year survival with current treatments, highlighting the urgent need to develop new and more effective therapeutic approaches for treating HCC. Hepatoblastoma (HB) is a rare malignant tumor of the liver in the pediatric population. It is found in 90% of cases before the age of three. 32 YAP1S127A withdrawal significantly regresses hepatoblastoma, implicating YAP1 as a therapeutic target for HB.33. While a novel T-cell therapy, ET140203 (ARTEMIS), has an orphan drug designation by the FDA for treating pediatric HB.34, no small-molecule drug is available for HB. Preoperative or postoperative chemotherapy remains the primary treatment and HB remains a deadly disease with unmet medical needs.
Researchers at the University of Florida have developed small molecule YAP-TEAD inhibitors for treating diseases with altered Hippo signaling. By targeting and blocking the activity of the YAP-TEAD transcriptional complex, these compounds are promising therapeutics for the treatment of HCC and HB while carrying low toxicity.
YAP-TEAD small molecule inhibitors for the treatment of diseases with altered Hippo signaling, such as HCC and HB
These small molecules target and inhibit TEAD proteins for treating diseases with altered Hippo signaling, such as Hepatocellular Carcinoma (HCC) and Hepatoblastoma (HB). Upon dysfunctional Hippo pathway regulation, YAP proteins translocate to the cell nucleus and interact with TEAD transcriptional factors to drive oncogenic transcriptional programs vital for cancer cell growth, survival, and epithelial-mesenchymal transition. These compounds covalently bind to the core pocket of TEAD through a cysteine residue on the protein, impairing the protein-protein interaction with YAP and depicting a potential therapeutic strategy for treating HCC and HB. In in vitro studies, the compounds show potent inhibition of YAP-related downstream genes and HCC and HB cell line growth. In in vivo studies, they significantly inhibit tumor growth in the xenograft and HB mouse models with no apparent toxicities.
These small molecules are inhibitors against protein arginine methyltransferase 5, which plays a role in tumor development and is overexpressed in several cancers, including lymphoma, glioblastoma, colorectal cancer, and prostate cancer. The global treatment market for these specific cancers should reach $58 billion by 2024. Additionally, inhibiting protein arginine methyltransferase 5 may be an effective treatment for inflammation and auto-immune disorders. Previously reported small molecule inhibitors of this protein have low potency or lack in vivo activity, limiting clinical applications.
Researchers at the University of Florida have developed competitive compounds that inhibit protein arginine methyltransferase 5 activity in cellular processes. These small molecules are effective in vivo and have a high potency, making them strong therapeutic candidates for the treatments of cancer and autoimmune disorders.
Competitive inhibitor compounds that block the activity of a cancer-associated protein and may be effective therapeutics against certain cancers, inflammation, and autoimmune disorders
This family of indole-based small molecules prevents S-adensylmethionine from binding to protein arginine methyltransferase 5, inhibiting the protein from participating in cellular processes associated with various cancers and autoimmune diseases. These small molecules have a 25-fold greater binding affinity and 40-fold greater efficacy than previous inhibitors of protien arginine methyltransferase 5.
These small-molecule interleukin-6 (IL-6) inhibitors target glycoprotein 130 (gp130) by blocking IL-6-gp130 signaling, delivering a cost-effective therapy for autoimmune diseases and IL-6-driven cancers. IL-6-gp130 signaling drives tumor growth and sustains chronic inflammation, making it a validated target in both oncology and autoimmunity. Existing antibody-based therapies are costly to produce and must be administered by injection, limiting patient access and scalability. With the IL-6 inhibitor market projected to exceed $35 billion, the current limitations underscore the need for a scalable and patient-friendly alternative to traditional biologic therapies that delivers comparable precision and efficacy in a more affordable and versatile form.
Researchers at the University of Florida have demonstrated that these advanced small-molecule IL-6 inhibitors offer better efficacy as anti-cancer agents, as well as for the treatment of inflammation. By selectively blocking IL-6 activity at its signaling receptor, these compounds halt the process that drives chronic inflammation and tumor progression, effectively reducing cancer cell growth and inflammatory signaling while preserving normal immune function. Their chemical stability and precise targeting make them well-suited for long-term use in autoimmune and inflammatory conditions such as rheumatoid arthritis and lupus, as well as IL-6–driven cancers.
These IL-6 inhibitors can be developed as orally available, cost-effective therapies for treating cancers and autoimmune or inflammatory diseases driven by IL-6 signaling
This class of small-molecule drugs introduces compounds that block interleukin-6 (IL-6) signaling by preventing the cytokine from activating its receptor complex. These compounds work by binding gp130, the key receptor component required for IL-6 signal transmission. By stopping gp130 from pairing with another receptor molecule, the drugs interrupt formation of the IL-6/IL-6Rα/gp130 complex that triggers the downstream STAT3 pathway, a key driver of inflammation and cancer growth. Repeated studies show the lead candidates attach directly to gp130 and lock it in an inactive state, confirming that the agents act at the start of IL-6 signaling rather than simply neutralizing the IL-6 protein itself.
