Research Interests:
The elderly population is dramatically increasing and aging is the primary risk factor for a majority of chronic diseases. Therefore, uncovering the molecular mechanisms of human aging, one of the great, unsolved mysteries in life sciences, is imperative in terms of the complexity of the science and also the importance to society. The major research areas in Wang's laboratory include but not limited to: 1) understanding the biology of aging from the angle of the systemic regulation of NAD biosynthesis in response to stress and aging; 2) development of new therapeutics for neurodegenerative diseases and cancer; 3) development of new methodologies for identification of drug target, which facilitates the biological discoveries using small molecules as probes. These efforts encompass a large spectrum of collaborative activities such as assay development, lead compound discovery and development, structural biology, neuroscience, medicinal chemistry, pharmacokinetic studies, in vivo efficacy studies, and so on.
Scientific Contributions:
Dr. Wang has been working in the field of chemical biology and developmental biology over the past decade. So far, her research has uncovered intracellular targets for several remarkable small-molecule probes, which hold promise to be developed toward clinical and commercial objectives. From these work she has discovered new strategies to promote caner cell death, and counteract neuronal cell death that are at the root of neurodegenerative diseases. Her early research provided insight of the complex regulation of Hedgehog signaling pathway, one of the major signaling pathways in animal development.
Selected Achievements
· Discovered P7C3 class of neuroprotective chemicals as the first small-molecule activates nicotinamide phosphoribosyltransferase (NAMPT) to protect against nerve cell death. The understanding of mode of action of P7C3 class of molecules revealed boosting NAD production as an efficient way for intervening neurological diseases and perhaps aging.
Figure 1：The model for the mode of action of P7C3 class of neuroprotective chemicals
· Discovered the first small-molecule activators of the TRAIL receptor DR5 from a high throughput screening of the small-molecule synergists of Smac mimetic. Much of the effort has been placed on finding a TRAIL-mimetic in the drug industry, because TRAIL is a much safer cancer cell-killing agent. Our compound will serve as a prototype of compound for further development of novel cancer drugs.
Figure 2：The model for the mode of action of a novel small-molecule agonist of Death Receptor 5
· Discovered the target of diazonamide A as ornithine aminotransferase (OAT). This study revealed the molecular basis for diazonamide toxicity and an unexpected role of OAT in mitotic cell division, and identified the protein as a novel target for cancer chemotherapeutic drug development.
· Mechanistic studies of the regulation of Hedgehog (Hh) signaling pathway. Abnormal regulation of Hh pathway leads to human cancers such as basal cell carcinoma. We used Drosophila as the model system to decipher the complex modulation of the culminating factor in the pathway - Cubitus interruptus (Ci) / Gli.
Figure 3：Complex regulation of Hedgehog signaling by Cos2.
Patents and Awards
2022 一种超碳金簇离子型化合物及其制备方法和应用。专利号：CN 113861226B
2020 新型NAMPT酶激动剂及其制备与用途。专利号：202011525254.7，PCT/CN2022/076187
2018 Chemical activators of Nicotinamide Mononucleotide Adenlyly Transferase 2 (NMNAT2) and uses thereof. Patent No.: PCT/CN2018/117723
2017 Neuroprotective compounds and methods for identifying and using same. Patent No.: US 9645139 B2
2009 Ornithine aminotransferase (OAT): a target for anticancer drugs. Patent No.: 7622289 B2 Career Development Award (Special Fellow), Leukemia & Lymphoma Society (2003-2006)
Selected Publications:
1. Yao, H.#, Liu, M.#, Wang, L.#, Zu, Y.#, Wu, C.#, Li, C., Zhang, R., Lu, H., Li, F., Chen, S., Gu, X., Liu, T., Yang, M., Hua, L., Tang Y.* and Wang, G.* (2022). Discovery of small-molecule activators of nicotinamidephosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity. Cell Research 32, 570-584.
2. Xiao, K.#; Zhang, N.#; Li, F.#; Hou, D.#; Zhai, X.; Xu, W.*; Wang, G.*; Wang, H.*; Zhao, L.* (2022). Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs. Nature Communications 13, 4669.
3. Wang, L. B.#; Liu, M. H.#; Zu, Y. M.#; Yao, H.; Wu, C.; Zhang, R. X.; Ma, W. N.; Lu, H. G.; Hua, L.; Wang, G.*; Tang, Y. F.* (2022). Optimization of NAMPT Activators to Achieve in vivo Neuroprotective Efficacy. European Journal of Medicinal Chemistry 236, 114260.
4. Gu, X.; Yao, H.; Kwon, I.*; Wang, G.* (2022). Small-molecule activation of NAMPT as a potential neuroprotective strategy, Life Medicine, https://doi.org/10.1093/lifemedi/lnac012.
5. Cai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022). The landscape of aging. Sci China Life Sci 65, https://doi.org/10.1007/s11427-022-2161-3
6. Lei, X. Q.; Li, Y. H.; Lai, Y.; Hu, S. K.; Qi, C.; Wang, G.*; Tang, Y. F.* (2021). Strain-Driven Dyotropic Rearrangement: A Unified Ring-Expansion Approach to α-Methylene-γ-butyrolactones. Angew. Chem. Int. Ed. 60, 4221–4230.
7. Wang, X., Zhou, J., Qi, C., Wang, G. (2019). Establishing cell lines overexpressing DR3 to assess the apoptotic response to anti-mitotic therapeutics. J. Vis. Exp. 143, e58705, doi:10.3791/58705.
8. Qi, C., Wang, X., Shen, Z., Chen, S., Yu, H., Williams, N. and Wang, G. (2018). Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells. Cell Research 28, 544-555.
9. Wang, G.#, Han, T.#, Nijhawan, D., Theodoropoulos, P., Naidoo, J., Yadavalli, S., Mirzaei, H., Pieper, A.A., Ready, J.M. and McKnight, S.L. (2014). P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158, 1324-1334.
10. Wang, G.*, Wang, X., Yu, H., Wei, S., Williams, N.S., Holmes, D.L., Halfmann, R., Naidoo, J., Wang, L., Li, L., Chen, S., Harran, P., Lei, X. and Wang. X. (2013). Small-molecule activation of the TRAIL Receptor DR5 in human cancer cells. (*First and co-corresponding author) Nature Chemical Biology 9, 84-89.
Commented by Stu Borman (2013). Small molecule makes cancer want to kill itself: agent is the first small molecule found to trigger death receptor on cancer-cell surfaces. Chemical & Engineering News, 91 (2): 37.
11. Wang, G., Shang, L., Burgett, A.W., Harran, P.G., Wang, X. (2007). Diazonamide toxin reveals a novel function for Ornithine Amino Transferase in mitotic cell division. PROC NAT ACAD SCI (USA) 104, 2068-2073.
12. Jia, J.#, Amanai, K.#, Wang, G.#, Tang, J., Wang, B., Jiang, J. (2002). Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416, 548-552.
13. Wang, G. and Jiang, J. (2004). Multiple Cos2/Ci complexes regulate Ci subcellular localization through microtubule dependent and independent mechanisms. Developmental Biology 268, 493-505.
14. Wang, G., Amanai, K., Wang, B., Jiang, J. (2000). Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of Cubitus interruptus. Genes & Development 14, 2893-2905.
15. Wang, G., Wang, B., Jiang, J. (1999). Protein Kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus. Genes & Development 13, 2828-2837.
16. Wang, G.*, Peng, Z., Shen, P. (2000). Cloning and overexpression of the tyrosinase mel gene from Pseudomonas maltophilia. (*First and corresponding author) FEMS Microbiology Letters 185, 23-27.
17. Jesús-Cortés, H.D., Xu, P., Drawbridge, J., Estill, S.J., Huntington, P., Tran, S., Britt, J., Tesla, R., Morlock, L., Naidoo, J., Melito, L.M., Wang, G., Williams, N.S., Ready, J.M., McKnight, S.L., and Pieper, A.A. (2012). Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease. PNAS 109, 17010-17015.
18. Gao, S., Wang, Q., Wang, G., Lomenick, B., Liu, J., Fan, C.W., Deng, L.W., Huang, J., Lum, L., Chen, C. (2012). The chemistry and biology of Nakiterpiosin – C-nor-D-Homos- teroids. Synlett 16, 2298-2310.
19. Zhang, W., Zhao, Y., Tong, C., Wang, G., Wang, B., Jia, J. and Jiang, J. (2005). Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Developmental Cell 8, 267-278.
20. Liu, Y., Wang, G., Zhao, R., Shen, P. and Qu, S. (2005). Microcalorimetric study on the growth of Escherichia coli HB101 effected by recombinant plasmid. ACTACHIMI- CASINICA 63, 327-331.
