Information about Dr. Xue’s current research projects can be found on this webpage.
Project 1: Therapeutics for diffuse large B-cell lymphomas (DLBCLs)
B-cell lymphoma 6 (BCL6) inhibitors — BCL6 is a transcriptional repressor of the BTB/POZ (bric à brac, tramtrack, broad complex/pox virus zinc finger) family. As the most commonly involved oncogene in DLBCLs; constitutive expression of BCL6 in GC B-cells causes DLBCL in mice. It is also frequently expressed in follicular lymphomas (FLs), and may be required for survival of these tumors as well. To be activated, BCL6 must bind to its co-repressor (e.g., SMRT, N-CoR and BCoR) through a unique interaction mediated by the N-terminal BTB domain. In collaboration with Professor Ari Melnick (the Weill Cornell Medical College), Professor Alexander MacKerell, and Professor Tomek Cierpicki (University of Michigan), we are developing small molecule inhibitors of the BCL6 BTB domain, to provide a novel candidates for future clinical trials. 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.
hCAR inhibitors — Current standard treatment of DLBCL involves the CHOP regimen. Although this combination therapy has resulted in improved survival for most patients, over 30% of DLBCL patients relapse due to intolerable side toxicities associated with currently used high dose of CHOP. As a key ingredient of the CHOP regimen, chemotherapy compound cyclophosphamide (CPA) is activated in human body by a process that is controlled by human constitutive androstane receptor (hCAR). In collaboration with Professor Hongbing Wang, we have shown that activation of hCAR by small molecule hCAR activators improves the anticancer effect of CPA in both cellular environment and animal models. Addition of hCAR activators to the CHOP regimen could decrease its efficacious dose by ~75%. At our current dose, the cardiovascular toxicity associated with CHOP was eliminated.
Project 2: Therapeutic agents for infectious diseases by targeting key factors in iron trafficking
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. The mechanism of action by new inhibitors on CRC cell growth are determined in vitro and in vivo. In collaboration with Professor Yan Shu, we are refining our 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 Professor 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.