Medical Management

MEI ZHANG, M.D., Ph.D.

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*** ******* ****, *********, ** 02421 781-***-****(C) 781-***-****(H)

**********@*****.***

SUMMARY

A MD and PhD scientist in cell biology with extensive experiences in mechanism of diseases, drug modes of

action, and small molecule drug discovery researches. Expertise in imaging-based molecular and phenotypic

analysis on mammalian cells including high content analysis. Specialized in creatively designing approaches for

difficult and complex cell-based assays. Leadership in coordinating multi-disciplinary tasks between biology

group and other functional groups for early stage of discovery program. Strong management skills in initiating,

developing, and negotiating outsourcing technologies. Disease areas include cancer, inflammation, metabolic

disease and neurodegeneration.

Highlights

Cell Biology and Imaging Drug Discovery Managerial Skills

Cell-based Assay Development Small Molecules Team Leader

Automation of Assay Platforms High Throughput Screening Project management

High Content Analysis Mechanism of Action Study Inter-group Communication

Live Cell Labeling GPCR and Calcium Channel Inter-department Communication

Immunofluorescence Cancer, Inflammation, Academic Collaboration and Assay

Confocal Microscopy Neurodegeneration Outsourcing

EXPERIENCE

2004 – 2009

Synta Pharmaceuticals

A mid-sized pharmaceutical company in Lexington MA, developing small molecule anti -cancer and

anti-inflammatory drugs.

Senior Scientist

Project Leader in Chemokine Receptor CXCR4 Inhibitor Program

Initiated and led CXCR4 program.

Designed and established 10 primary and secondary screening assays.

Streamlined FLIPR screening of 30,000 compounds, which significantly resulted in reduced processing

time.

Advanced program to hit-to-lead development.

Validated 6 chemical scaffolds of functional inhibitors.

Strategized and led outsourcing effort for certain assays.

Coordinated with computational and medicinal chemists for SAR analysis.

Initiated collaboration with academic labs in Children’s Hospital and Harvard Medical School.

Head of Cellular Imaging Laboratory, Biology Department

Established functional imaging center equipped with digital imaging system, video-microscopes, high

content imaging system, with high volume imaging database management.

Pioneered the use of GFP technology to facilitate drug discovery and development in the company.

Developed multiple assays using live cell labeling technologies for high content analysis.

Developed time-lapse platform for analyzing cardiomyocyte contraction function for ion channel

modulators in vitro.

Lead Scientist in Vascular Disrupting Agent Program

Discovered a group of microtubule inhibitor hits from drug candidates from an unrelated project.

Unraveled the mechanism of action of the inhibitors in cellular assays.

Facilitated hit-to-lead and early lead optimization for drug candidates.

Lead Scientist for Mechanism of Action Studies of Phase 2 and 3 drugs (Apilimod and Elesclomol)

Identified endosomes and lysosomes as important cellular targets for Apilimod.

Determined roles of multiple Toll-like receptors in Apilimod’s action in inhibiting NFkB (c-Rel) and

IL12/IL23.

Discovered centrosome and proteasome as important cellular targets for Elesclomol.

Helped in the elucidation of Elesclomol’s activity of generating reactive oxygen species (ROS).

2003 – 2004

Massachusetts General Hospital / Harvard Medical School

In Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General

Hospital, Charlestown, MA

Research Fellow

Alzheimer’s disease and neurodegenerative disease research

Led the discovery of role of presenilins/gamma-secretase in regulating endocytosis of amyloid precursor

protein (APP).

Introduced GFP technology and improved imaging system for Alzheimer’s disease research in the

laboratory.

Designed and developed assay for live cell analysis on gamma-secretase inhibitors and APP trafficking.

Extensive experience with confocal microscopy to determine cellular compartments with various

endosomal markers including Rib 3,7,9 and 11 proteins, transferrin, dextran and GFP-chimera.

Extensive experience with human stem cell line expressing wild type or mutant enzymes for Alzheimer’s

disease research.

1997– 2003

National Institutes of Health (NIH)

In Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and

Kidney Diseases (NIDDK), Bethesda, Maryland

Research Fellow

Lysosomal storage disease and neurodegeneration research

Discovered and characterized novel cellular machinery in protein and lipid trafficking, and its defect in

lysosomal storage diseases (Niemann-Pick type C disease and mucolipidosis type IV).

Analyzed multiple monoclonal antibodies and polyclonal antibodies for immunofluorescence, protein

trafficking, cell function and target identification.

Introduced GFP-chimera technology to evaluate antibody specificity in cell membrane, fixed cells and live

cells.

Established digital imaging analysis system for intracellular cholesterol trafficking and the diagnosis of

lysosomal storage disease (including Niemann-Pick type C disease and mucolipidosis type IV).

Established GFP, RFP, YFP and CFP technology for fluorescence protein-based assays using confocal

imaging system.

1993 – 1997

Shanghai Institute for Pediatric Research

In Department of Pediatric Endocrinology, Genetics and Metabolism, Shanghai Institute for

Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,

Shanghai, China

Post-Doctoral Research Fellow

Research and clinic study on genetic metabolic diseases

Screened patient DNA from Southern Chinese phenylketonuria (PKU).

Discovered novel mutations and applied the analysis in clinical genetic tests.

Established a molecular genetic laboratory for genetic metabolic diseases.

1988 – 1993

West China University of Medical Sciences (now Sichuan University)

In Department of Pediatric Hematology, the Affiliated Women and Children’s Hospital of the

university. Chengdu, China

PhD Candidate, Sichuan University Medical Center, China

Residency and Chief Residency trainings in pediatric hematology/oncology department of the university

teaching hospital

Systemic training of bone marrow morphology analysis on hematology/oncology diseases

Carried out pediatric hematology and oncology researches

EDUCATION

Ph.D. Pediatric Hematology, Clinical Medicine, West China University of Medical Sciences (Sichuan

University) 1993

M.D. Clinical Medicine, West China University of Medical Sciences (Sichuan University) 1988

Biotechnology training

High Content Analysis Course (SBS 2008); ImageExpress Micro System (MDC 2008); AcuityExpress HCS and

Image Database Management (MDC 2008); Medicinal Chemistry Concept for Biologists (SBS 2008); Zeiss 410

Confocal Imaging System (NIH 1998)

SKILLS

Small molecule screening

FLIPR HTS screening

High content screening (HCS) and high content analysis (HCA)

Transwell chemotaxis

HTS compound handling and management

In Vitro Imaging (Cell biology and pathology)

Bright field microscopy, Fluorescence microscopy, Quantitative imaging, Time-lapse imaging, High resolution

tissue microscopy

Bone marrow smear and analysis for hematology and oncology diseases

Imaging instrumentation and other systems

HCS system: Molecular Devices ImageExpress Micro (IXMicro)

Nikon microscope systems: TE300, TE2000 with CoolSnap HQ CCD, Hamamatsu EM CCD cameras

Incubator-based microscopes: Essen IncuCyte

Confocal systems: Zeiss 410 system, 510 Pascal system

FLIPR system: Molecular Devices FLIPR 384

FlexStation plate reader: Molecular Devices FlexStation II

HPLC: Agilent HPLC system

Computer software

Imaging acquisition / browsers: IPLab, Zeiss LSM Imaging Browser, MetaMorph, MetaExpress, AcuityExpress

HTS: FLIPR Software

Data process: Excel and XLFit

Compound management: DS Accord for Excel, ChemDraw

Imaging processing: Adobe Photoshop, Image J, CellProfiler

Cell biology

Protein localization: immunofluorescence

Analysis of cellular dynamics: Chemotaxis; cell migration; HUVEC tube formation; cardiomyocyte contraction

Cytometry analysis: FACS sorting and GFP-expression cell subcloning; organellar trafficking

Live cell labeling: GFP techniques; protein translocation; free cholesterol; lipid droplets; cell proliferation;

apoptosis; cell cycle; cytotoxicity; reactive oxygen species (ROS)

Cell culture and subcloning: Mammalian primary cells (cardiomyocytes, neurons, astrocytes, macrophage,

endothelial cells, stem cells, bone marrow cells); co-culture; cell fusion; cancer cell lines; subcloning of GFP

expressing cells

Transfection: Amaxa system; electroporation; chemical transfection

Virus mediated transfection: Lentivirus, adenovirus and retrovirus

Molecular biology

Molecular cloning; cDNA library construction; site-directed mutagenesis; lentivirus/adenovirus/retrovirus vector

cloning; real time PCR (Taqman); RNAi; nucleic acid hybridization

Biochemistry

Immunoblotting; protein expression; protein purification in bacterial and human cells; enzyme analysis; receptor

and ligand binding assays; fluorescence-based detection of ROS (hydroxyl radical generation) through copper-

based redox reaction

APPLICATION OF CELL-BASED ASSAYS

1. Elucidation of cellular mechanisms for human disease:

a. Niemann-Pick C disease (NPC) (Late endosomal tubular trafficking defects) (@NIH)

b. Mucolipidosis IV (ML4) (Protein trafficking defects and calcium accumulation in lysosomes) (@NIH)

c. Alzheimer’s disease (AD) (Reduction of early endocytic recycling, accumulation of g-secretase substrates

in ERC) (@MGH)

d. Cancer metastasis (Role of SDF1 and CXCR4 axis in metastasis) (@Synta Pharma)

e. Tumor vasculature (Role of microtubule in vascular structure) (@Synta Pharma)

f. Tumor angiogenesis (Roles of HSP90 and CXCR4) (@Synta Pharma)

g. Cancer and cell stress (Roles of ROS and HSP70 in cancer) (@Synta Pharma)

h. Inflammation (TLR9 activation by CpG and cRel trafficking) (@Synta Pharma)

i. Inflammation and T cell calcium influx (CRACM1 and Stim1 trafficking) (@Synta Pharma)

2. Localization of membrane and soluble proteins in intracellular organelles:

a. Plasma membrane (CXCR4, S1P1, CRACM1) (@Synta Pharma)

b. Early endosomes (APP and APP-C99) (@MGH)

c. Late endosomes (NPC1, NPC2, MLN64, ML4, and activated CXCR4) (@NIH and Synta Pharma)

d. Lysosomes (NPC1, NPC2, MLN64, Mucolipin-1, and activated CXCR4) (@NIH and Synta Pharma)

e. Mitochondria (MLN64-cholesterol acceptor) (@NIH and Synta Pharma)

f. Endoplasmic reticulum (Mutant NPC1 and Mucolipin-1, Stim-1) (@NIH)

g. Golgi apparatus (FcER) (@NIH)

h. Centrosome (Proteasome inhibitor, Aurora-kinase B)(@Synta Pharma)

i. Microtubules (Alpha-tubulin, Spag6) (@NIH and Synta Pharma)

j. Actin filaments (16Q) (@NIH)

k. Proteasome (Tubulin-YFP) (@Synta Pharma)

l. Nuclei (16Q) (@NIH)

m. Nucleoli (Proteasome substrates) (@Synta Pharma)

n. Lipid droplets (Hexosaminidase C short form) (@NIH)

o. Peroxisomes (Marker) (@NIH)

3. Tracking lipid location, trafficking and abnormalities:

a. Cholesterol (@NIH)

b. Glycolipids (@NIH)

c. Neutrolipids (@NIH)

d. Ceramide (@Synta Pharma)

4. Study modes of action of new drugs in discovery and development:

a. Apilimod (C-Rel translocation, ERK translocation, Vacuolation) (@Synta Pharma)

b. Elesclomol (Proteasome inhibition, and induction of ROS and OH radical generation) (@Synta Pharma)

c. Microtubule inhibitors (Existing and new inhibitors: fragmentation of MT and multinucleation) (@Synta

Pharma)

d. CRAC inhibitors (Effect on cardiomyocytes) (@Synta Pharma)

e. Synergistic anti-cancer effects (Elesclomol with paclitaxel or ascorbate) (@Synta Pharma)

5. Contribution to new drug discovery programs

a. VDA Program (@Synta Pharma)

b. CXCR4 Inhibitor Program (@Synta Pharma)

SELECTED PUBLICATIONS

1. Zhang M. Endocytic mechanisms and drug discovery in neurodegenerative diseases. Front Biosci. 2008

May 1; 13:6086-105.

2. J Kirshner, S He, V Balasubramanyam, J Kepros, CY Yang, M Zhang, Z Du, J Barsoum, and J Bertin.

Elesclomol Induces Cancer Cell Apoptosis through Oxidative Stress. Mol Cancer Ther. 2008 Aug;

7(8):2319-27.

3. Tauzin L, Graf C, Sun M, Rovina P, Bouveyron N, Jaritz M, Winiski A, Hartmann N, Staedtler F, Billich A,

Baumruker T, Zhang M, and Bornancin F. Effects of ceramide-1-phosphate on cultured cells: dependence

on dodecane in the vehicle. J Lipid Res 2006 48:66-76.

4. Zhang M, Haapasalo A, Kim DY, MacKenzie Ingano LA, Pettingell WH, and Kovacs DM. Presenilin/g-

secretase activity regulates protein clearance from the endocytic recycling compartment. FASEB J 2006; 20:

1176-1178.

5. Zhang M, Sun M, Dwyer NK, Comly ME, Patel SC, Sundaram R, Hanover JA, Blanchet te-Mackie EJ.

Differential trafficking of the Niemann-Pick C1 and 2 proteins highlights distinct roles in late endocytic

lipid trafficking. Acta Paediatr Suppl 2003 Dec; 92(443):63-73.

6. Zhang M, Liu P, Dwyer NK, Christenson LK, Fujimoto T, Martinez F, Comly M, Hanover JA, Blanchette-

Mackie EJ, Strauss JF 3rd. MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic

mitochondria. J Biol Chem 2002 Sep 6; 277(36):33300-10.

7. Zhang M, Dwyer NK, Love DC, Cooney A, Comly M, Neufeld E, Pentchev PG, Blanchette-Mackie EJ,

Hanover JA. Cessation of rapid late endosomal tubulovesicular trafficking in Niemann -Pick type C1 disease.

Proc Natl Acad Sci USA 2001 Apr 10; 98(8):4466-71.

8. Zhang M, Dwyer NK, Neufeld EB, Love DC, Cooney A, Comly M, Patel S, Watari H, Str auss JF 3rd,

Pentchev PG, Hanover JA, Blanchette-Mackie EJ. Sterol-modulated glycolipid sorting occurs in Niemann-

Pick C1 late endosomes J Biol Chem 2001 Feb 2; 276(5):3417-25.

9. Zhang M, Hsiao K, Su T, Chao H, Chen R, Gu X. Two novel mutations in phenylalanine hydroxylase gene

and in vitro expression analysis on mutation Arg252Gln. Chinese Med Sci J. 1997; 12(1):22-5.

INVITED SPEECHES

1. Cholesterol accumulation inhibits late endosomal tubular trafficking in Niemann-Pick Type C cells.

Protein trafficking workshop, 2001. National Institutes of Health, National Institute of Diabetes and

Digestive and Kidney Diseases.

2. A high speed time-lapse video platform for analyzing effects of GPCR and ion-channel modulators on

cardiomyocyte contraction. IBC’s 13th Annual World Congress on Drug Discovery & Development of

Innovative Therapeutics (DDT) August 4, 2008 World Trade Center Boston, MA.

3. Development of high speed videomicroscopy platform for analysis of cardiomyocyte contraction . 4th

Annual New England Users' Meeting, 4th of August, 2008; Le Meridien Hotel, Cambridge, MA.

PATENTS

1. Compounds acting at the centrosome (PCT Patent 2006 International Patent Number WO 2006/062732 A2).

2. Compounds for the treatment of proliferative disorders (PCT Patent 2 006 International Patent Number

PCT/US2006/005761).

3. Compositions and methods for modulating cytokine production (Pub. No. WO/2007/100631).

AWARDS

Honored Student Awards in College; China Post Doctoral Research Award and Grants; Chesapeake Microscopy

Association Best Microscopy Award; Chesapeake Microscopy Association Young Scientist Award; Synta Halo

Award for Scientific Achievement; CEO’s Synta Spirit Award; CEO’s Synta-related Art Award

SOCIETIES

Member, Sigma Xi, Honorary Scientific Research Society

Member, the American Society for Cell Biology

Member, the Society for Bimolecular Sciences

Member, the Frontiers in Biosciences

RESIDENCE STATUS

US Permanent Residence

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