Cutaneous Biology Research Center

photo

Xu Wu, Ph.D.

My research is focused on studying cellular functions (self-renewal, differentiation, proliferation, and chromatin remodeling) and developmental signaling pathways using chemical and genomic tools.

More information can also be found here: Wu Lab

 

Welcome to the Wu lab website! We are a new lab at CBRC, MGH/Harvard Medical School, located at the MGH-Charlestown Navy Yard, Building 149.


We are interested in using chemical biology and functional genomics to investigate cell signaling pathways that are involved in the regulation of stem cell fate and tumorigenesis, as well as essential cellular functions such as terminal differentiation, senescence, and quiescence. Our goal is to discover novel therapeutic targets and agents for the treatment of degenerative diseases and cancers.

Xu Wu, PhD

Principal Investigator, MGH

Assistant Professor, Harvard Medical School

B.S. Chemistry, Peking University

M.S. Biological Chemistry, University of Pennsylvania

Ph.D. Chemistry, The Scripps Research Institute

Before joining the faculty of MGH/HMS, Xu was a PI and Director of Biological Chemistry at Genomics Institute of the Novartis Research Foundation (GNF) for 6 years. He has been working on chemical biology and drug discovery for regenerative medicine and cancer.

 

Michael DeRan, Ph.D
Postdoctoral Research Fellow

mderan@partners.org

B.S. Biochemistry, St. Bonaventure University

M.S. Biochemistry, University of Rochester

Ph.D. Biochemistry,  University of Rochester

Michael finished his Ph.D in Biochemistry at Prof. Jiyong Zhao’s lab at University of Rochester. His Ph.D work was focused on NPAT-mediated transcriptional regulation of histone gene during cell cycle, and the function of NPAT in DNA damage. Michael is now investigating the signaling crosstalks of Hippo pathway and other essential signaling pathways using chemical tools.

Baohui Zheng, Ph.D
Postdoctoral Research Fellow

B.S. and M.S. Chemistry, Nankai University

Ph.D. Organic Chemistry,  Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS)

Baohui was trained as an organic chemist at Prof. Xue-Long Hou’s lab at SIOC/CAS. His Ph.D work was focused on Pd-Catalyzed asymmetric allylic substitution reaction. Baohui is now working on medicinal chemistry and chemical biology of novel modulators of pathways that controls stem cell fate and tumorigenesis.


Xinyan Li, Ph.D
Visiting Scholar/Research Fellow

B.A, Medicine, Nanjing Medical University

M.A. Pharmacology, Dalian Medical University

Ph.D. Pharmacology, China Pharmaceutical University

Xinyan is a visiting scholar from Shanghai Jiaotong University. She worked on high throughput screening and mechanistic studies of liver cirrhosis before. Her current work is to develop novel chemical biology tools to study Hedgehog and Hippo pathways and protein palmitoylation.

 

Chemical Biology and Functional Genomics of Regeneration and Cancer
One of the important aspects of life science research is to understand human diseases at the molecular level and develop therapeutics targeting the disease relevant gene products. It remains challenging to develop new therapeutics with a traditional “target-based” approach, mainly because 1) Many of the disease relevant genes are not easily “druggable”. 2) Many human diseases are highly complex and involve multiple factors. It is difficult, and maybe unrealistic, to identify a “magic bullet” for such diseases. Therefore, it would be important to develop new strategies to understand cellular signaling networks and how they are “rewired” in diseases. Such work might reveal the critical “nodes” of the signaling network, allowing the development of effective therapeutics. Our group is interested in using chemical and functional genomics approaches to study signaling networks and cellular processes in diseases, aiming to discover novel chemical modulators and pharmacologically validate new therapeutic targets for cancer and degenerative diseases.

1. Chemical approaches for posttranslational protein palmitoylation


The covalent attachment of lipid moieties is an essential modification of proteins. S-palmitoylation is a dynamic and reversible process.  Cys-rich DHHC-family of palmitoyl acyltransferases (PATs) have been shown to catalyze palmitoylation, and other protein acyl transferase might also exist. Dynamic palmitoylation of proteins has been linked to the regulation of membrane attachment, trafficking and signaling activities of membrane bound receptors, kinases, and G-proteins.

Although palmitoylation is an important posttranslational modification, the detailed mechanisms and its function in signal transduction are largely unknown, due to the lack of proper tools and probes to dissect this process. There are at least 23 DHHC containing PATs in human genome, and their functions are elusive.

To this end, we are interested in using combinatorial synthesis, affinity-based proteomics and medicinal chemistry to address the key questions of this modification: 1) What are the substrates for each of the PATs and are there other proteins that catalyze such reaction?  2) What are the functions of dynamic palmitoylation in signal transduction? 3) Can we develop specific inhibitors for PATs and acylprotein thioesterases (APTs) to dissect the dynamic regulations?

2. Chemical approaches to dissect signal cross-talking and “rewiring” in degenerative diseases and cancer
Cellular behaviors are regulated by a complex network of signal transduction pathways. The precise coordination and orchestration of multiple signaling pathways are essential for proper cellular functions.  In diseases like cancer, oncogenic events often “rewire” the signaling network, resulting aberrant cell growth, survival and motility through non-canonical signaling cascades. Identification of small molecule tools that regulate the “nodes” of the crosstalks would be very important to understand the “rewired” signaling network and develop novel and effective therapeutics.

One essential question that we would like to understand is how cell growth is coordinated through multiple signals including growth factors, cell-cell contact and nutrients. We developed high throughput screening strategies to interrogate the signaling networks involving Hedgehog, Wnt and Hippo signaling, and their interactions with other key signaling pathways. We are developing novel chemical modulators of these networks, and pharmacologically validating novel therapeutic targets for cancer and degenerative diseases.


3. Chemical and functional genomic approaches for cellular senescence and terminal differentiation
Cellular senescence is characterized as irreversible cell cycle exit as a result of cells reaching their proliferation limit or under oncogenic stress, and is often linked to aging and serves as a barrier for oncogenic transformation. Small molecule and genetic factors that modulate cellular senescence and terminal differentiation would be useful to reveal novel mechanisms underlying these processes and provide new therapeutic approaches for cancer.

We are interested in discovering new chemical tools that modulate cellular senescence, reinstall oncogene-induced senescence in cancer cells; and induction of terminal differentiation of stem cells, progenitors and cancer cells. We will investigate the mode of action of these tools and pharmacologically validate the new targets.

1. Haiyan Tao, Qihui Jin, Dong‐In Koo, Xuebing Liao, Nathan P. Englund, Yan Wang, Peter G. Schultz, Marion Dorsch, Joseph Kelleher, and Xu Wu*, “Small Molecule Antagonists in Distinct Binding Modes Inhibit Drug Resistant Mutant of Smoothened” 2011, Chemistry & Biology, 18, 1-6.

2. Jun Liu, Kristen Johnson, Jie Li, Victoria Piamonte, Brian M. Steffy, Mindy Hsieh, Nicholas Ng, Jay Zhang, John R. Walker, Sheng Ding, Ken Muneoka, Xu Wu, Richard Glynne, Peter G. Schultz* “A Regenerative Phenotype in Mice with a Point Mutation in TGFBR1” 2011, Proc Natl Acad Sci U S A. Submitted.

3. Silvia Buonamici, Juliet Williams, Anlai Wang, Ribo Guo, Anthony Vattay, Kathy Hsiao,Jing Yuan, John Green, Lance Ostrom, Paul Fordjour, Dustin L. Anderson, Michael Morrissey, John E. Monahan, Joseph F. Kelleher, Stefan Peukert, Shifeng Pan, Xu Wu, Sauveur‐Michel Maira, Carlos Garcia‐Echeverria, Kimberly J. Briggs, D. Neil Watkins, Yungmae Yao, Christoph Lengauer, Markus Warmuth, William R. Sellers, Marion Dorsch*, “Targeting resistance to Smoothened antagonists by inhibiting the PI3K pathway” Science Translational Medicine, 2010, 2, 51ra70.

4. Hans Skvara, Frank Kalthoff, Marion Dorsch, Joseph Kelleher, Xu Wu, Shifeng Pan, Lesanka Mickel, Christopher Schuster, Georg Stary, Ahmad Jalili, Olivier David, Ana Monica Costa Antunes, Arthur P. Bertolino, Anton Stuetz, Kristine Rose, Georg Stingl, Menno A. De Rie* “Topical treatment of Basal cell carcinomas, occurring in patients with Gorlin’s syndrome, with a Smoothened inhibitor” Journal of Investigative Dermatology, 2011, published online on March 22, doi:10.1038/jid.2011.48

5. Xiaoyi V. Hu, Tania M. A. Rodrigues, Haiyan Tao, Robert K. Baker, Loren Miraglia, Anthony P. Orth, Gary E. Lyons*, Peter G. Schultz* and Xu Wu*, “A Functional Genomics Screen Identifies RNF4 as a Regulator of DNA Demethylation” 2010, Proc Natl Acad Sci U S A. 107(34):15087-92

6. Shifeng Pan*, Xu Wu, Jiqing Jiang, Wenqi Gao, Yongqin Wan, Dai Cheng, Dong Han, Jun Liu, Nathan P. Englund, Yan Wang, Stefan Peukert, Karen Miller‐Moslin, Jing Yuan, Ribo Guo, Melissa Matsumoto, Anthony Vattay, Yun Jiang, Jeffrey Tsao, Fangxian Sun, AnneMarie C. Pferdekamper, Stephanie Dodd, Tove Tuntland, Wieslawa Maniara, Joseph F. Kelleher, III, Yung‐mae Yao, Markus Warmuth, Juliet Williams and Marion Dorsch, “Discovery of NVP‐ LDE225, a Potent and Selective Smoothened Antagonist” ACS Med. Chem. Lett. Published online, 2010, DOI: 10.1021/ml10003077.

7. Yahua Liu, Qiang Ding and Xu Wu* “Concise Regiospecific Synthesis of 5‐chloropyrido[4,3‐ d]pyrimidin‐4(3H)‐one” Synthesis, 2010, No. 1, 0030–0032x

8. Xu Wu and Peter G. Schultz* “Synthesis at the Interface of Chemistry and Biology” Journal of the American Chemical Society, 2009; 131(35):12497‐515.
           This paper is the first JACS Perspectives published in 130 yrs history of the flagship journal of American Chemical Society.
           JACS Perspectives is a new series of review articles for JACS to capture the new concepts and interdisciplinary chemical research.            Highlighted by JACS editor. J. Am. Chem. Soc., 2009, 131 (35).
           Highlighted in Chemical & Engineering News.


9. Shoutian Zhu, Heiko Wurdak, Yan Wang, Anna Galkin, Haiyan Tao, Jie Li, Costas Lyssiotis, Feng Yan, Bu Tuu, Loren Miraglia, John Walker, Fanxiang Sun, Anthony Orth, Jennifer Harris, Peter G. Schultz* and Xu Wu* “A genomic screen identifies TYRO3 as a MITF regulator in melanoma ” Proc Natl Acad Sci U S A. 2009; 106(40):17025‐30

10. Shoutian Zhu, Heiko Wurdak, Jian Wang, Costas A. Lyssiotis, Eric C. Peters, Charles Cho, Xu Wu*, and Peter G. Schultz* “A Small Molecule Primes Embryonic Stem Cells for Differentiation” Cell Stem Cell 2009; 4(5):416‐426.

        Highlighted in Nature Chemical Biology 5, 456­457 (2009). Endowing Endoderm.
        Highlighted in Cell Stem Cell 4, 373­374 (2009). Using Small Molecules to Great Effect in Stem Cell Differentiation.

        Highlighted in Molecular Interventions 9, 167 (2009). Stauprimide: A Small Molecule Directs Stem Cells to Differentiate.

 

11. Weidong Wang, John R. Walker, Xia Wang, Matthew S. Tremblay, Jae Wook Lee, Xu Wu, and Peter G. Schultz* “Identification of small‐molecule inducers of pancreatic β‐cell expansion” Proc Natl Acad Sci U S A. 2009;106(5):1427‐32.

12. Yahua Liu, Qiang Ding and Xu Wu* “Rearrangement of N,N‐Di‐tert‐butoxycarbonyl‐pyridin‐4‐ amines and Formation of Polyfunctional Pyridines” The Journal of Organic Chemistry 2008; 73(15):6025‐8.

13. Jongkook Lee, Xu Wu, Maria Pasca di Magliano, Eric C. Peters, Yan Wang, Jiyong Hong, Matthias Hebrok, Sheng Ding, Charles Y. Cho, Peter G. Schultz. “A Small‐Molecule Antagonist of the Hedgehog Signaling Pathway.” Chembiochem. 2007; 8(16):1916‐1919.

14. Costas A. Lyssiotis, John Walker, Chunlei Wu, Toru Kondo, Peter G. Schultz* and Xu Wu* “Inhibition of Histone Deacetylase Activity Induces Developmental Plasticity in Oligodendrocyte Precursor Cells” Proc Natl Acad Sci U S A. 2007 104(38):14982‐7.

        Highlighted in Cell 131, 197­198 (2007). Leading Edge: Glial Precursors Break Their Commitment.

15. Yibing Qyang, Silvia Martin‐Puig, Murali Chiravuri, Shuibing Chen, Huansheng Xu, Lei Bu, Xin Jiang, Lizhu Lin, Anne Granger, Alessandra Moretti, Leslie Caron, Xu Wu, Jonathan Clarke,Makoto M. Taketo, Karl‐Ludwig Laugwitz, Randall T. Moon, Peter Gruber, Sylvia M. Evans, Sheng Ding, and Kenneth R. Chien* “The Renewal and Differentiation of Isl1+ Cardiovascular Progenitors Are Controlled by a Wnt/β‐Catenin Pathway" Cell Stem Cell, 2007 16;1(2):165‐79.

 

16. Jun Liu, Xu Wu, Brian Mitchell, Chris Kintner, Sheng Ding and Peter G. Schultz* “Small Molecule Agonists of the Wnt Signaling Pathway” Angew. Chem. Int. Ed.2005. 44. 2‐4.

 

17. Xu Wu, John Walker, Jie Zhang, Sheng Ding and Peter G. Schultz* “Purmorphamine Induces Osteogenesis by Activation of Hedgehog Signaling Pathway” Chemistry & Biology, 2004, 11(9), 1229‐38.

        This work has been reported by many news agencies, including Bio.com and has been reviewed in several renowned scientific   journals.

 

18. Shuibing Chen, Qisheng Zhang, Xu Wu, Peter G. Schultz*, and Sheng Ding* “Dedifferentiation of Lineage‐Committed Cells by a Small Molecule” Journal of the American Chemical Society, 2004, 126 (2), pp 410–411

19. Xu Wu, Sheng Ding and Peter G. Schultz* “Small molecule Inducers of Cardiomyogenesis in Embryonic Stem Cells” Journal of the American Chemical Society, 2004, 126(6), 1590‐1591.

      This work has been reported by many news agencies, including American Chemical Society news center, Modern Drug Discovery       and Palm Beach Post, and has been  reviewed in several renowned scientific journals.

20. Xu Wu, Sheng Ding, Qiang Ding, Nathanael S. Gray and Peter G. Schultz* “A Small Molecule with Osteogenesis‐Inducing Activity in Multipotent Mesenchymal Progenitor Cells” Journal of the American Chemical Society, 2002, 124(49), 14520‐14521.
        This work has been reviewed in several renowned scientific journals.

21. Sheng Ding, Nathanael S. Gray*, Qiang Ding, Xu Wu and Peter G. Schultz* “Resin‐capture and release strategy toward combinatorial libraries of 2,6,9‐substituted purines.” Journal of Combinatorial Chemistry, 2002, 4(2), 183‐186.

22. Sheng Ding, Nathanael S. Gray*, Xu Wu, Qiang Ding and Peter G. Schultz* “A combinatorial scaffold approach toward kinase‐directed heterocycle libraries.” Journal of the American Chemical Society, 2002, 124(8), 1594‐1596.

23. Bari A. Pender, Xu Wu, Paul H. Axelson, and Barry S. Cooperman* “Toward a Rational Design of Peptide Inhibitors of Ribonucleotide Reductase: Structure‐Function and Modeling Studies.” Journal of Medicinal Chemistry, 2001, 44(1), 36‐46.

24.Xu Wu and Barry S. Cooperman* “Synthesis and biological activity of bivalent inhibitor of mouse ribonucleotide reductase.” Bioorganic and Medicinal Chemistry Letters, 2000, 10, 2387‐2389

Patents

 25. Ding, Qiang; Okram, Barun; Uno, Tetsuo; Liu, Yahua; Jin, Yunho; Jin, Qihui; Wu, Xu; Che, Jianwei; Liu, Hong; He, Xiaohui; Zhu, Xuefeng; Yang, Kunyong.Compounds and compositions as kinase inhibitors. Provisional Patent Filed.

 26. Zhu, Shoutian; Wurdak, Heiko; Wang, Yan; Tao, Haiyan; Schultz, Peter G; Wu, X; Tyro3 as a therapeutic target for melanoma. Provisional Patent Filed.

27. Okram, Barun; Uno, Tetsuo; Ding, Qiang; Liu, Yahua; Jin, Yunho; Jin, Qihui; Wu, Xu; Che, Jianwei; Yan, S. Frank.Compounds and compositions as kinase inhibitors.PCT Int. Appl. (2009), 324pp. CODEN: PIXXD2 WO 2009097287 A1 20090806 AN 2009:944707CAPLUS

28. Dierks, Christine; Warmuth, Markus; Wu, Xu.Biphenylcarboxamide derivatives as hedgehog pathway modulators.PCT Int. Appl. (2008),76pp. CODEN: PIXXD2 WO 2008154259 A1 20081218 CAN 150:48036 AN 2008:1502750CAPLU

29. Gao, Wenqi; Jiang, Jiqing; Wan, Yongqin; Cheng, Dai; Han, Dong; Wu, Xu; Pan, Shifeng. Substituted biphenyl amide compounds and compositions as hedgehog pathway modulators.PCT Int. Appl. (2007),60 pp. CODEN: PIXXD2 WO 2007131201 A2 20071115 CAN 147:534706 AN 2007:1303209CAPLUS

30. Wu, Xu; Ding, Sheng; Schultz, Peter G.Compounds and compositions as hedgehog pathway modulators.PCT Int. Appl. (2006),28 pp. CODEN: PIXXD2 WO 2006050351 A2 20060511 CAN 144:445331 AN 2006:440130CAPLUS

31. Wu, Xu; Ding, Sheng; Schultz, Peter G.2,4­Diaminopyrimidines as inducers of cardiomyogenesis, their preparation and use in the treatment of cardiomyopathy.PCT Int. Appl. (2005),56 pp. CODEN: PIXXD2 WO 2005068437 A1 20050728 CAN 143:172888 AN 2005:673272CAPLUS

32. Wu, Xu; Ding, Sheng; Gray, Nathanael S.Purine derivatives for inducing osteogenesis.U.S. Pat. Appl. Publ. (2004),33 pp. CODEN: USXXCO US 2004157864 A1 20040812 CAN 141:185125 AN 2004:654776CAPLUS

Cutaneous Biology Research Center

Building 149
13th Street
Charlestown, MA 02129

Phone: 617-726-4354


Directions to Charlestown Navy Yard MGH East - Building 149

From Storrow Drive

  • From the end of Storrow Drive (Leverett Circle) keep to the far right and take a sharp right (do not go up the ramp), and continue beneath the underpass one quarter mile to the light.
  • Turn left onto Causeway street under the elevated subway tracks. The Fleet Center will be on your left, the North Station T station on your right.
  • One block past the Garden, turn left on to N. Washington Street, passing over the Charlestown Bridge. 
  • At the first light after the bridge, take a right. Go through three traffic control lights. 
  • At the fourth light, turn right into Navy Yard (Gate 5 - 13th Street). To park, take first left onto Fifth Avenue. Building 149 is one block on the right.
  • The parking garage entrance is on the right about half way down the block.
From 93 North
  • Take the Mass Pike (I-90) to I-93 North (Exit 24B)
  • Take the Storrow Drive Exit (Exit 26)Stay in the left lane once getting on the exit ramp. Follow signs for North Station/Leverett Circle Go through 1 light and take left at the 2nd light (almost immediately after the first)
  • Get immediately into the right lane 
  • Take a right at the light onto Route 28N 
  • The Museum of Science will be on your left 
  • Take a right at the 3rd light (there is a sign at the corner for Charlestown) 
  • Go over the bridge and get in the right lane (City Square)
  • Take your 1st right and get into the left lane 
  • Turn left at the 2nd light (immediately before Charlestown Bridge, at City Square) onto Chelsea Street (If you go over bridge, you've gone too far). 
  • Go through three traffic control lights
  • At the 4th light, turn right into the Navy Yard (Gate 5 - 13th Street).
  • To park, take first left onto Fifth Avenue. Parking Garage entrance is on the right above half way down the block. Building 149 is one block on the right once you turn into Gate 5. Building 149 is also connected to the parking garage.
From 93 South
  • Take Exit 28 (Charlestown/Sullivan Square).
  • At the end of the exit where the read forks stay to the right and proceed past the bus terminal to the rotary at Sullivan Square.
  • Go halfway around the rotary towards Charlestown (the Schrafts building with a large American flag on top of it will be on your left).
  • Cross the railroad tracks and take a left at the fire station onto Medford Street.
  • At the end of Medford street turn left onto Chelsea Street and make an immediate right into the Navy Yard.
  • The MGH East Research Building (Bldg. 149) will be on the right and is connected to the parking garage by overhead walkways.
By Taxi
  • Direct the driver to the MGH East, Building 149 in the Charlestown Navy Yard.
  • The CBRC is on the 3rd Floor of Building 149.
By Public Transportation & the MGH/Partners Shuttle
  • Take the T (Green Line) to North Station
  • Take the MGH/Partners Shuttle bus to the Charlestown Navy Yard MGH East Research Building (Building 149). 
  • The CBRC is on the 3rd Floor.
  • The MGH/Partners Shuttle bus leaves MGH on Blossom Street and stops at North Station on Canal Street by the Green Line T stop. The shuttle goes every 15 minutes during working hours. (Less often on the weekends and holidays).
The CBRC
  • To get to the CBRC, take the first set of elevators to the left of the main entrance by the Security Desk to the third floor. You may need to check in with security on the main level of Building 149.
  • From the elevator, exit to the East to the CBRC offices, or in the opposite direction for the laboratories.