Scientist/Chemist

MOHAMMED TAIMI, Ph.D.

*** ******* ****, *********, ** 02421- Tel. 781-***-****, Cell 781-***-****

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Summary

o Twelve years of industrial experience in DMPK with demonstrated ability to build and manage a high-performing DMPK group

o Areas of expertise include pharmaceutical sciences, drug metabolism and pharmacokinetics (DMPK), analytical chemistry, bioanalysis and medicinal chemistry.

o Strong experience and leadership in vitro and in vivo ADME/PK studies to support drug development program from early drug discovery, lead optimization, candidate selection and preclinical development

o Extensive project management skills and proven ability to work as part of a team of medicinal chemists, pharmacologists, toxicologists and serving as a mentor for DMPK-related issues, attending cross-functional project team meetings, interpreting and presenting data

PROFESSIONAL EXPERIENCE

2006-present Principal Scientist , DMPK, Synta Pharmaceuticals, Lexington, MA

2001-2006 Project Leader, DMPK; Cytochroma Inc. Markham, ON

1999-2001 Senior Scientist, Drug Metabolism; Cytochroma Inc. Markham, ON

EDUCATION

1993-98 Postdoctoral Fellow, National Cancer Institute, NIH, Bethesda, MD

1989-1992 Ph. D. in Biochemistry; University of Montpellier II, Montpellier, France

1989, M. Sc. University of Montpellier II, Montpellier, France

1988 B.S., Aix-Marseille University, Marseille, France

KEY PROFESSIONAL ACCOMPLISHMENTS

Utilized experience in quantitative bioanalysis, drug metabolism, pharmacokinetics and metabolite identification to make positive impacts on several drug discovery programs

o Successfully designed and implemented an integrated ADME/PK screening strategy (in vitro and in vivo) to support development of novel drug candidates from early discovery, lead-optimization, preclinical development 

o Developed and validated several in vitro and in vivo assays to assess drug exposure and investigate issues related to ADME/PK 

In vitro screening studies:

o Implemented standard DMPK screening including: solubility in GI fluids, caco-2 permeability, metabolic stability (clearance), plasma protein binding, CYP inhibition (LC/MS rapid cocktail screening assay, IC50, Ki values, and evaluation of TDI), CYP induction, CYP phenotyping and drug transporters (ABC ATPase, functional bidirectional assays)

Metabolite Identification

o Performed and leaded qualitative bioanalytical analysis for Metabolite Identification studies in various species both in vitro (hepatocytes) and in vivo (plasma, bile and tissues samples)

o Investigated Met. ID data and closely discuss with medicinal chemistry group to design compounds with improved clearance properties

o Evaluated species metabolism difference and discussed with toxicology group for selecting appropriate species for preclinical toxicology studies

o Validated bioactivation assays to evaluate reactive metabolite formation and established risk mitigation strategy for nominating lead candidates for development

In vivo studies:

o Experienced in PK analysis and interpretation: rodent PK (noncompartmental), TK, dose-dependency PK, excretion studies in bile-cannulated rat, and tissue distribution studies

o Familial with all aspect of non-rodent PK studies (dog, monkey): evaluate exposure level, clearance, therapeutic index, interspecies scaling, and human first dose prediction

I

o Developed in vitro and in vivo models (IVIVC) for absorption, bioavailability, clearance and MAD

o Explored PK simulation, PK/PD, PBPK (WinNonLin, GastroPlus, SimCYP) to simulate exposure in various species, investigate parameter sensitivity analysis and predict first in human dose

DMPK Management

o Prioritized ADME/PK data and evaluated drug-like properties for go-no go decision and candidate selection for oral and IV applications

o Regularly investigate Structure Property Relationship (SPR) and closely discuss with Medicinal Chemistry group to design compounds with improved properties

o Championed in the implementation of ADME/PK nomination criteria in early discovery stage (first-in-class vs. best-in-class) and participated in a multidisciplinary drug discovery team including chemists (medicinal, drug product), pharmacologists and toxicologists for nominating lead candidates for preclinical development

o Supported preclinical development and contributed in evaluating DMPK data and in writing sections of regulatory documents in support of lead compounds entering human clinical trials.

o Expanded DMPK capabilities: Hired and trained several staff scientists and research associates, mentored students in the research projects

o Participated in budgeting and strategic planning for discovery projects, managed outsourcing activities when needed and purchased analytical instruments (LC/MS)

Awards

o Recipient of 2007 Synta Pharmaceuticals Achievement Galactic award for outstanding contributions in several projects

Key accomplishments at National Cancer Institute NIH, Bethesda, MD

The research program was related on elucidating the molecular mechanism of drug resistance in cancer cells in response to small molecules modulating nuclear receptor signaling pathways. Using bioanalytical skills (HPLC, LC/MS), we explored metabolizing enzyme genes involved in biosynthesis of key signaling molecules involved in cell growth and differentiation. Overall, the studies suggested that resistant cancer cells to signaling molecules acquire high potential to metabolize natural regulatory molecules and therefore escape cell differentiation and apoptosis. The project was supervised by Dr. T.R. Breitman (who discovered the therapeutic benefit of retinoic acid in leukemia patients); and funded by Cancer Therapeutic Program at the National Cancer Institute, NIH.

PUBLICATIONS

1. Parise R. A., Egorin M. J., Kanterewicz B., Taimi M., Petkovich M., Lew A. M., Chuang S. S., Nichols M., El-Hefnawy T., and P. A. Hershberger. 2006. CYP24, the enzyme that catabolizes the antiproliferative agent vitamin D, is increased in lung cancer. International Journal of Cancer 119 (8):1819-28.

2. Taimi M., Helvig C., Wisniewski J., Ramshaw H., White J., Amad M., Korczak B. and Petkovich M. 2004. A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-transisomers of retinoic acid. J. Biol. Chem. 279 (1):77-85.

3. Chuang SS., Helvig C., Taimi M., Ramshaw HA., Collop AH., Amad M., White JA., Petkovich M., Jones G., and Korczak B. 2004. CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and (omega-1)-hydroxylation of fatty acids. J. Biol. Chem. 279 (8):6305-14.

4. Taimi M, Breitman TR and Takahashi N. 2001. Cyclic AMP-dependent protein kinase isoenzymes in human myeloid leukemia (HL60) and breast tumor (MCF-7) cells. Arch Biochem Biophys.392 (1):137-44.

5. White JA., Ramshaw H., Taimi M., Stangle W., Zhang A., Everingham S., Creighton S., Tam SP., Jones G. and Petkovich M. 2000. Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism. Proc Natl. Acad. Sci. U S A. 97 (12):6403-8.

6. Taimi M., Chen ZX. and Breitman TR. 1998. Potentiation of retinoic acid-induced differentiation of human acute promyelocytic leukemia NB4 cells by butyric acid, tributyrin, and hexamethylene bisacetamide. Oncol. Res. 10 (2):75-84.

7. Muccio DD., Brouillette WJ., Breitman TR., Taimi M., Emanuel PD., Zhang X., Chen G., Sani BP., Venepally P., Reddy L., Alam M., Simpson-Herren L. and Hill DL. 1998. Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias. J. Med. Chem. 41(10):1679-87.

8. Parker BW., Kaur G., Nieves-Neira W., Taimi M., Kohlhagen G., Shimizu T., Losiewicz MD., Pommier Y., Sausville EA. and Senderowicz AM. 1998. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 91(2):458-65.

9. Taimi M. and Breitman TR. 1997. N-4-hydroxyphenylretinamide enhances retinoic acid-induced differentiation and retinoylation of proteins in the human acute promyelocytic leukemia cell line, NB4, by a mechanism that may involve inhibition of retinoic acid catabolism. Biochem. Biophys. Res. Commun. 232 (2):432-436.

10. Taimi M. and Breitman TR. 1997. Growth, differentiation, and death of retinoic acid-treated human acute promyelocytic leukemia NB4 cells. Exp. Cell. Res. 230 (1):69-75.

11. Taimi M., Dornand J., Nicolas M., Marti J. and Favero J. 1994. Involvement of CD4 in interleukin-6 secretion by U937 monocytic cells stimulated with the lectin jacalin. J. Leukoc. Biol. 55 (2):214-20.

12. Cellier MF., Taimi M., Chateau MT., Cannat A. and Marti J. 1993. Thermal stress as an inducer of differentiation of U937 cells. Leuk. Res. 17 (8):649-56.

13. Taimi M., Defacque H., Commes T., Favero J., Caron E., Marti J. and Dornand J. 1993. Effect of retinoic acid and vitamin D on the expression of interleukin-1 beta, tumour necrosis factor-alpha and interleukin-6 in the human monocytic cell line U937. Immunology 79 (2):229-35.

14. Taimi M., Defacque H., Commes T., Favero J., Dornand J. and Marti J. 1993. The retinoic acid analog CBS-211A potentiates the 1 alpha,25-dihydroxyvitamin D3-induced differentiation of U937 cells. Agents Actions 38 (1-2):91-9.

15. Taimi M., Chateau MT., Cabane S. and Marti J. 1991. Synergistic effect of retinoic acid and 1,25- dihydroxyvitamin D3 on the differentiation of the human monocytic cell line U937. Leuk Res. 15 (12):1145-52.

16. Taimi M., Chateau MT., Marti J. and Pacaud M. 1990. Induction of differentiation of the human histiocytic lymphoma cell line U937 in the absence of vimentin expression. Differentiation 45 (1):55-60.

RECENT ABSTRACTS

Mohammed Taimi, Keizo Koya and Noriaki Tatsuta. October 2008. CYP Inhibition Throughput Assays for Assessing Drug-Drug Interaction Potential in Early Drug Discovery and Lead Optimization. ISSX 2008, San Diego, California

Taimi M., Shin L., Dong Y., Lu YF., and Tatsuta N. November 2007. Solubility in Simulated Gastric

Fluid as an Important Factor in Predicting Oral Bioavailability and Improving PK Properties. AAPS

2007, San Diego, California.

Chuang, S. S., Taimi, M., Lew, A. M., Kharebov, A., Nickerson, L., Collop, A. H., Posner, G. H., and

B. Korczak. April 2005. Novel Vitamin D Signal Amplifier inhibits both cancer cell growth and CYP24

enzymatic activity. American Association for Cancer Research (AACR) 2005. Anaheim, California.

Korczak, B., Lew, A., Chuang, S. S., Helvig, C., Taimi, M., and G. H. Posner. May 2005. Vitamin D

agonist and CYP24 inhibitor- a novel therapeutic approach. 2nd International symposium: Vitamin D

analogs in cancer prevention and therapy. Lübeck, Germany. Oral presentation.

Taimi M. Nicherson L., Patton L. Petkovich M. and Korczak B. June 2004. CYP26 genes mRNA

expression, RA-metabolic activity, and antiproliferative activity in response to retinoic acid in cancer

cell lines in vitro and in vivo. FASEB retinoid meeting Callaway Gardens Resort Pine Mountain, GA.

Taimi M., Helvig C., White J. A., Petkovich M., and B. Korczak. July, 2003. CYP26C, A novel human

cytochrome P450 involved in metabolism of all-trans and 9-cis-RA retinoic acid. 13th International

Conference on Cytochromes P450, Prague, Czech Republic.

Helvig C., Chuang S. S., Taimi M., Jones G., Petkovich M., White J. A. and B. Korczak. July, 2003.

CYP2U1, a thymus and cerebellum expressed cytochrome P450 converts arachidonic acid into

bioactive derivatives 19- and 20-HETE. 13th International Conference on Cytochromes P450,

Prague, Czech Republic.

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