Information about Dr. Xue’s current research projects can be found on this webpage.
Project 1: B-cell lymphoma 6 (BCL6) inhibitors as novel therapeutic agents for diffuse large B-cell lymphomas (DLBCLs)
BCL6 is a transcriptional repressor of the BTB/POZ (bric à brac, tramtrack, broad complex/pox virus zinc finger) family of proteins. It is the most commonly involved oncogene in DLBCLs; constitutive expression of BCL6 in GC B-cells causes DLBCL in mice. BCL6 is required for survival of DLBCL cells and can limit their ability to respond to DNA damaging agents. It is also frequently expressed in follicular lymphomas (FLs), and may be required for survival of these tumors as well. DLBCL and FL collectively constitute ~60-70% of B-cell lymphomas and the incidence of these tumors has been rising in recent decades. To be activated, BCL6 must bind to its co-repressor (e.g., SMRT, N-CoR and BCoR) through a tight and unique interaction mediated by the N-terminal BTB domain. Our recent results showed that peptides that mimic the SMRT interface can displace SMRT from BCL6, de-repress BCL6 target genes and kill DLBCL cells. However, important limitations such as poor metabolic stability and membrane permeability restrict their clinical application. In collaboration with Professor Ari Melnick (the Weill Cornell Medical College) and Professor Alexander MacKerell, we are developing small molecule inhibitors to the BTB domain of BCL6 to directly address these clinical limitations, and provide a novel strategy to drug candidates for future clinical trials. Using crystallographic analysis and computer aided drug design (CADD) we have identified a small molecule (79-6) that binds to the BTB domain and displace SMRT from its repression complex with BCL6. This compound specifically re-activates BCL6 target genes, kills BCL6 dependent DLBCL cells in vitro, suppresses already established DLBCL tumors in mice, kills primary DLBCL cells from human patients ex vivo, and is non-toxic in animals. Recently, a new lead compound (FX1, JCI 2016, 126, 3351.) derived from 79-6 has shown improved potency while keeping the pharmacokinetic characteristics of 79-6. Currently, we are optimizing the pharmacodynamic (PK) and pharmacokinetic (PD) properties of the inhibitors.
Project 2: Therapeutic agents for infectious diseases by targeting key factors in iron trafficking
Novel heme transporter inhibitors — the trypanosomatid parasites L. major and L. amazonensis are causative agents of human cutaneous leishmaniasis. They are responsible for an estimated 2 million new infections annually. In mammals, Leishmania is an obligate intracellular parasite, replicating inside macrophages in the amastigote form. Treatment of leishmaniasis still relies on toxic drugs (e.g., pentavalent antimony), which requires high doses and lengthy courses of treatment. To sustain their growth and reproduction, parasites exhibit distinct adaptations that allow them to acquire nutrients from the host. An example of such a nutrient uptake process is heme, which is synthesized by all vertebrates (hosts). It is shown that the free-living roundworm C. elegans and parasitic nematodes cannot synthesize heme, but instead acquires heme from their environment or host via heme transporters. Correspondingly, protozoa such as Leishmania and Trypanosoma are also dependent on exogenous heme. In collaboration with Professor Iqbal Hamza (University of Maryland at College Park), we are designing and synthesizing novel antagonists for heme transporters to elucidate the structure, mechanism and regulation of the heme transporters, validate them as novel targets for treating parasitic infections, and provide novel compounds as drug candidates.
Bacterial heme oxygenase inhibitors — multi-drug resistant (MDR) Pseudomonas aeruginosa causes infections that show resistance to many available antibiotics and creates a dangerous threat to human health. Moreover, P. aeruginosa is intrinsically resistance to many current antibiotics, which makes it a severe healthcare problem. Heme utilization as a source of iron in P. aeruginosa is key for its virulence mechanism. Blocking the release of iron from heme by targeting bacterial HemO, a key enzyme that catalyzes the oxidative cleavage of the porphyrin macrocycle to biliverdin and carbon monoxide (CO) with the release of iron, therefore, represents a novel strategy for the development of new antibiotics that reduces the selective pressure on the bacteria to develop resistance. In collaboration with Professor Angela Wilks, we designed and synthesized new inhibitors of bacterial HemO based on recently synthesized lead compounds; the binding epitope of the inhibitors were determined using STD-NMR experiments the anti-microbial activity of the new inhibitors are evaluated by multiple biological assays.
Project 3: Therapeutics targeting the Wnt/β-catenin signaling pathway
Anti-Colorectal Cancer agent— Colorectal cancer (CRC) causes over 50,000 annual death in the U.S. Wnt/β-catenin signaling pathway is essential to cell proliferation, organ development, and differentiation. Over 90% CRC patients carry generic mutations associated with upregulation of the Wnt/β-catenin signaling pathway. Using pyrvinium as a template, we have developed pyrazole-based inhibitors, of which, YW2065 inhibits Wnt/β-catenin signaling activity with an IC50 value of 73 nM. Moreover, YW2065 indicated promising efficacy against CRC cell growth both in vitro and in vivo, is nontoxic in mice. Our studies are intended to test the hypothesis that novel, rationally designed small molecules with improved pharmacological properties can safely inhibit the Wnt/β-catenin signaling pathway and ultimately be used to treat CRC. Specifically we will refine the chemical structure of new lead YW2065 by synthesizing three classes of new inhibitors. The mechanism of action by new inhibitors on CRC cell growth will be determined in vitro and in vivo. We will also assess the cellular permeability, metabolic stability, pharmacokinetics, and toxicity for the optimal compounds. Moreover, we will perform the modern proteomic strategy thermos protein profiling (TPP) to identify the protein target of selected new inhibitors. At the conclusion of the studies, we anticipate to develop novel inhibitors of the Wnt/β-catenin signaling pathway with the understanding of its mechanism of action. The resulting knowledge will greatly benefit future research in understanding the pathophysiology of Wnt/β–catenin pathway and open an avenue to therapeutic development. In collaboration with Professor Yan Shu, we are designing and synthesizing novel pyrazole-based Wnt inhibitors with improved drug-like profiles. We are also trying to identify the protein target of new inhibitors using modern proteomic methods (e.g., TPP) or pull-down experiments using biotinylated ligands.
Anti-Nonalcoholic fatty liver disease agent — Non-alcoholic fatty liver disease (NAFLD) affects more than 30% of Americans due to the growing individuals with metabolic disorders, including obesity, metabolic syndromes and diabetes. At present, there are no approved pharmacological options for NAFLD and its clinical sequela non-alcoholic steatohepatitis (NASH). Genetic downregulation of Wnt/β-catenin has been demonstrated to improve diet-induced NAFLD in mice. In collaboration with Yan Shu, We have designed, synthesized and tested a novel class of triazole-based compounds of which a lead compound YW1128 potently inhibits Wnt/β-catenin signaling activity. YW1128 showed an exciting efficacy against hepatic steatosis in vitro and in vivo in mice. It was well tolerated in mice without any apparent toxicity.