Design C

DAVID J. RICHARD, PhD

** ********* **** ****

Littleton, MA 01460

215-***-**** (cellular)

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

SUMMARY

. Skilled medicinal chemist/team leader with pharmaceutical and biotech

experience in the

discovery, design, and advancement of small molecule therapeutics

. Experience in all areas of small molecule preclinical discovery and

analog design, including hit

triage, hit-to-lead, and lead development

. Project leader with understanding of relevant biological assays,

experience in selection of

appropriate biochemical, biological, and pharmaceutical profiling

assays

. Extensive knowledge of synthetic organic chemistry theory and practice,

including the multi-step

syntheses of complex molecules such as heterocycles and macrocycles

. Experience in interpreting structural biology information and utilizing

advanced computational

chemistry tools

. Keen understanding of the relationship between compound structural and

physicochemical

attributes and compound pharmacokinetics and experience in the

optimization of such properties

. Skilled in analysis of patent literature, utilization of such information

for analog design, and

composition of patent applications

. Expertise in the design of synthetic sequences which may be effectively

carried out by external

resources and experience in the management of external chemistry FTEs

. Co-inventor of a class of urea derivatives, a member of which has been

utilized to produce a clinical

candidate for oncology (PF-05212384)

. Documented impact on medicinal chemistry projects as evidenced by patent

application and

publication record

MEDICINAL CHEMISTRY EXPERIENCE

Eutropics, Cambridge, MA; Director of Drug Discovery and Development

June 2011-April 2013

Medicinal Chemistry Team Leader: Protein-Protein Interaction Inhibitors for

Oncology

. Successfully advanced primary series from initial hit to lead

optimization stage, designing

and identifying analogs which displayed on-target activity and in

vivo efficacy

. Identified alternative scaffold within secondary series to allow for

enhanced IP

. Coordinate collaborative research efforts with multiple academic

collaborators and

CROs including ADME, tolerability, PK, efficacy, and advanced

biological assays

. Assist in identification and design of appropriate primary and

follow-up biological assays

. Supervise studies which utilize Eutropics' proprietary functional

biomarker, in addition

to traditional biomarkers, to validate on-target activity

. Efficiently utilize chemistry resources to develop focused analog

strategy, and design

synthetic routes which allowed for preparation by external

resources with high success rate

. Analyze intellectual property space, develop Eutropics' small

molecule therapeutic patent

strategy, and compose applications (3 to date)

. Supervise internal FTE biologists and coordinate efforts of external

chemistry FTEs

Pfizer Research, Cambridge, MA; Principal Scientist

Oct. 2009-June 2011

Development of Kinase Inhibitors for Inflammation

. Developed routes and completed syntheses of a variety of

alternative cores, resulting in two

proprietary lead series with excellent potency

David J. Richard

Page 2

. Served as lead author for provisional patent application reporting

these discoveries

. Drew upon data from patent literature and fragment-based screening

results to design a

hybrid inhibitor with dramatically improved (200-fold) biochemical

potency and

enhanced physicochemical properties

. Designed numerous chemical libraries and oversaw preparation by

external resources . Extensively utilized computational chemistry

to guide analog design

Wyeth Research, Pearl River, NY; Senior Research Scientist I/II

Nov. 2006-Oct. 2009

Development of Selective mTOR Inhibitors for Oncology

. Designed and synthesized pyrazolopyrimidines as mTOR kinase

inhibitors for oncology

. Utilized computer-assisted drug design and molecular modeling to

guide analog

preparation and identify sites for the incorporation of

water-solubilizing groups

. Gained knowledge of oncology biology and strategies for the

development of kinase

inhibitors

. Investigated alternative scaffolds to improve

pharmacokinetic properties

. Contributed to the development of SAR for three chemical

series

. Developed analogs with improved microsomal stability and solubility

while maintaining

excellent cellular activity

ACADEMIC EXPERIENCE

Princeton University, Postdoctoral Associate

2004-2006 Mentor: Professor Erik J. Sorensen

. Developed strategies directed toward the total syntheses of the

indole alkaloid chartellamide

A and the anti-malarial sesquiterpene paulitin

. Served as mentor to two graduate and three undergraduate research

students

University of Pennsylvania, Graduate Assistant

1998-2004

Ph. D., Organic Chemistry, University of Pennsylvania, Philadelphia, PA,

2004

Advisor: Professor Madeleine M. Joulli

Thesis: Chapter 1: "Total Synthesis of Tamandarin B"

Chapter 2: "Synthesis of Isoroquefortine C and a Novel Related

Heterocycle"

. Completed the first total synthesis of the biologically active

depsipeptide natural product

tamandarin B

. Conducted studies towards the synthesis of the indole alkaloid

roquefortine C and

completed the first syntheses of isoroquefortine C

Bates College, Undergraduate Researcher

1994-1998

B. S., Chemistry (cum laude), Bates College, Lewiston, ME, 1998

Advisor: Professor Thomas Wenzel

Thesis: "Synthesis of Chiral Lanthanide Shift Reagents"

PATENT AND PATENT APPLICATIONS

Richard, D.J.; Cardone, M. Methods and Compositions Useful for Treating

Diseases Involving BCL-2 Family Proteins with Isoquinoline and Quinoline

Derivatives. Application No. 61/729,251, November 26, 2012.

Richard, D.J.; Cardone, M. Methods and Compositions Useful for Treating

Diseases Involving BCL-2 Family Proteins with Quinoline Derivatives.

Application No. 61/662,084, July 5, 2012.

David J. Richard

Page 3

Cardone, M.; Kolodjiecz, A.; Richard, D. J. Compositions and Methods Useful

for Treating Diseases. WO2012122370, March 8, 2012.

Venkatesan, A. M.; Chen, Z.; Dehnhardt, C. M.; Dos Santos, O.; Delos

Santos, E. G.; Zask, A..; Verheijen, J. C.; Kaplan, J. A.; Richard, D. J.;

Ayral-Kaloustian, S.; Mansour, T. S.; Gopalsamy, A.;

Curran, K. J.; Shi, M. Triazine Compounds as pI3 Kinase and mTOR

Inhibitors. US 8,039,469, issued October 18, 2011.

Richard, D. J.; Papaioannou, N.; Dehnhardt, C.; Nguyen, T.; Lovering, F.;

Kaila, N.; Thorarensen, A. Imidazopyridazines and Imidazopyridines as

Therapeutic Agents. Provisional application PC071772, February 9, 2011.

Verheijen, J. C.; Zask, A.; Richard, D. J.; Kaplan, J. A.; Curran, K. J.

Pyrimidine Compounds, their Use as mTOR and PI3 Kinase Inhibitors for

Treating Cancer, and their Syntheses. WO2010120998, October 21, 2010.

Zask, A.; Verheijen, J. C.; Kaplan, J. A.; Curran, K. J.; Ayral-Kaloustian,

S.; Richard, D. J. Preparation of Ureidoaryl- and Carbamoylaryl-bridged

Morpholinopyrimidine Derivatives for use as mTOR and PI3 Kinase Inhibitors.

WO2010120987, October 21, 2010.

Venkatesan, A. M.; Chen, Z.; Dehnhardt, C. M.; Dos Santos, O.; Delos

Santos, E. G.; Zask, A..; Verheijen, J. C.; Kaplan, J. A.; Richard, D. J.;

Ayral-Kaloustian, S.; Mansour, T. S.; Gopalsamy, A.; Curran, K. J.; Shi, M.

Triazine Compounds as pI3 Kinase and mTOR Inhibitors. WO2009143317,

November 26, 2009.

Venkatesan, A. M.; Chen, Z.; Dehnhardt, C. M.; Dos Santos, O.; Delos

Santos, E. G.; Zask, A..; Verheijen, J. C.; Kaplan, J. A.; Richard, D. J.;

Ayral-Kaloustian, S.; Mansour, T. S.; Gopalsamy, A.; Curran, K. J.; Shi, M.

Triazine Compounds as pI3 Kinase and mTOR Inhibitors. WO2009143313,

November 26, 2009.

Zask, A.; Kaplan, J. A.; Verheijen, J. C.; Curran, K. J.; Richard, D. J.;

Ayral-Kaloustian, S. Thienopyrimidine and Pyrazolopyrimidine Compounds and

their Use as mTor Kinase and pI3 Kinase Inhibitors. US2009098086, April 16,

2009.

Zask, A.; Nowak, P. W.; Verheijen, J.; Curran, K. J.; Kaplan, J.; Malwitz,

D.; Bursavich, M. G.; Cole, D. C.; Ayral-Kaloustian, S.; Yu, K.; Richard,

D. J.; Lefever, M. Pyrazolopyrimidine Analogs and their Use as mTor Kinase

and pI3 Kinase Inhibitors. WO2008115974, September 25, 2008.

PUBLICATIONS

Richard, D. J.; Carlson, N.; Lena, R.; Pierceall, W.; Bannister, T.;

Spicer, T.; Hodder, P.; Cardone, M. BH3 Profiling as a Functional Biomarker

for Validation of a Selective Mcl-1 Inhibitor. Mol. Cancer Ther.,

manuscript submitted.

Pierceall, W.E.; Carlson, N.E.; Elashoff, M.; Richard, D.J.; Huang, X.;

Konopleva, M.; Kornblau, S.M.; Cardone, M.H.; Andreeff, M. BH3 Profiling is

a Predictive Biomarker for Response to Cytarabine-based Treatment of Acute

Myelogenous Leukemia. Blood, manuscript submitted.

Verheijen, J. C.; Richard, D. J.; Zask, A. Non-Protein Kinases as

Therapeutic Targets. In Kinase Drug Discovery (RSC Drug Discovery Series);

Ward, R. A., Goldberg, F. W., Ed. RSC Publishing: Cambridge, UK, 2012, 19,

161-217.

Zask, A.; Verheijen, J. C.; Richard, D. J. Recent Advances in the Discovery

of Small Molecule ATP-competitive mTOR Inhibitors: a Patent Review. Expert

Opin. Ther. Pat. 2011, 21, 1109-1127.

David J. Richard

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Moore, W. J.; Richard, D. J.; Thorarensen, A. An Analysis of the Patent

Estates of Rigel and Portola: Amidopyrimidine SYK Inhibitors. Expert Opin.

Ther. Pat. 2010, 20, 1703-1722.

Richard, D. J; Verheijen, J. C.; Zask, A. Recent Advances in the

Development of Selective, ATP-Competitive Inhibitors of mTOR. Curr. Opin.

Drug. Discov. Devel. 2010, 13, 428-440.

Richard, D. J.; Verheijen, J. C.; Yu, K.; Zask, A. Triazines Incorporating

(R)-3-Methylmorpholine are Potent Inhibitors of the mammalian Target of

Rapamycin with Selectivity over PI3K?. Bioorg. Med. Chem. Lett. 2010, 20,

2654-2657.

Verheijen, J. C.; Richard, D. J.; Curran, K.; Kaplan, J.; Yu, K.; Zask, A.

2-Arylureidophenyl-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines as

Highly Potent and Selective ATP-Competitive mTOR Inhibitors: Optimization

of Human Microsomal Stability. Bioorg. Med. Chem. Lett. 2010, 20, 2648-

2653.

Zask, A.; Verheijen, J. C.; Richard, D. J.; Kaplan, J.; Curran, K.; Toral-

Barza, L.; Lucas, J.; Hollander, I.; Yu, K. Discovery of 2-

Ureidophenyltriazines Bearing Bridged Morpholines as Potent and Selective

ATP-Competitive mTOR Inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 2644-

2647.

Curran, K. J.; Verheijen, J. C.; Kaplan, J.; Richard, D. J.; Toral-Barza,

L.; Hollander, I.; Lucas, J.; Ayral-Kaloustian, S.; Yu, K.; Zask, A.

Pyrazolopyrimidines as Highly Potent and Selective, ATP-Competitive

Inhibitors of the mammalian Target of Rapamycin (mTOR): Optimization of the

1-Substituent. Bioorg. Med. Chem. Lett. 2010, 20, 1440-1444.

Richard, D. J.; Verheijen, J. C.; Curran, K.; Kaplan, J.; Toral-Barza, L.;

Hollander, I.; Lucas, J.; Yu, K.; Zask, A. Incorporation of Water-

Solubilizing Groups in Pyrazolopyrimidine mTOR Inhibitors; Discovery of

Highly Potent and Selective Analogs with Improved Human Microsomal

Stability. Bioorg. Med. Chem. Lett. 2009, 19, 6830-6835.

Verheijen, J.; Richard, D. J.; Curran, K.; Kaplan, J.; Lefever, M.; Nowak,

P.; Malwitz, D. J.; Brooijmans, N.; Toral-Barza, L.; Zhang, W.-G.;

Hollander, I.; Ayral-Kaloustian, S.; Mansour, T.; Yu, K; Zask, A. Discovery

of 4-Morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as Highly Potent and

Selective ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin

(mTOR). J. Med. Chem. 2009, 52, 8010-8024.

Zask, A.; Kaplan, J.; Verheijen, J. C.; Richard, D. J.; Curran, K.;

Brooijmans, N.; Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-

Kaloustian, S.; Yu, K. Morpholine derivatives greatly enhance the

selectivity of mammalian target of rapamycin (mTOR) inhibitors. J. Med.

Chem. 2009, 52, 7942-7945.

Zask, A.; Verheijen, J.; Kaplan, J.; Curran, K.; Richard, D. J.;

Brooijmans, N.; Lucas, J.; Toral-Barza, L.; Zhang, W.-G.; Hollander, I.;

Gibbons, J.; Abraham, R.; Ayral-Kaloustian, S.; Mansour, T.; Yu, K. Design

and Synthesis of Potent and Selective ATP Competitive Inhibitors of the

Mammalian Target of Rapamycin. J. Med. Chem. 2009, 52, 5013-5016.

Richard, D. J.; Schiavi, B.; Joulli , M. M. Synthetic Studies of

Roquefortine: Synthesis of Isoroquefortine C and a New Heterocycle. Proc.

Natl. Acad. Sci. U.S.A. 2004, 101, 119**-*****.

Joulli , M. M.; Richard, D. J. Cyclopeptide Alkaloids: Chemistry and

Biology. Chem. Comm. 2004, 18, 2011-2015.

Hadden, C. E.; Richard, D. J.; Joulli , M. M.; Martin, G. E. Natural

Product Synthesis with Unnatural Results: Characterization of a Novel Fused

Imidazolidinone Tetrahydropyrroloindole Ring System by Long-Range P1PH-

P15PN 2D NMR. J. Het. Chem. 2003, 40, 359-362.

Schiavi, B.; Richard, D. J.; Joulli , M. M. Total Synthesis of

Isoroquefortine C. J. Org. Chem. 2002, 67, 620-624.

David J. Richard

Page 5

Liang, B.; Richard, D. J.; Portonovo, P.; Joulli , M. M. Total Syntheses

and Biological Investigations of Tamandarins A and B and Tamandarin A

Analogs. J. Am. Chem. Soc. 2001, 123, 4469-4474.

Joulli , M. M.; Portonovo, P.; Liang, B.; Richard, D. J. Total Synthesis

of -Tamandarin B. Tetrahedron Lett. 2000, 41, 9373-9376.

ORAL PRESENTATIONS

Richard, D. J.; Verheijen, J. C.; Curran, K.; Kaplan, J.; Brooijmans, N.;

Yu, K.; Toral-Barza, L.; Lucas, J.; Hollander, I.; Zhang, W.-G.; Ayral-

Kaloustian, S.; Mansour, T.; Zask, A. Synthesis and Anti-Tumor Properties

of Pyrazolopyrimidines: Potent, ATP Competitive, and Selective Inhibitors

of the Mammalian Target of Rapamycin (mTOR). American Chemical

Society/American Association for Cancer Research "Chemistry in Cancer"

Meeting, New Orleans, LA, 2009.

Richard, D. J.U; Chen, W. C.; Joulli , M. M. Progress Toward the Total

Synthesis of Roquefortine C. Abstracts of Papers, 222nd National Meeting of

the American Chemical Society, Chicago, IL, 2001; ORGN 171.

Richard, D. J.U; Liang, B.; Portonovo, P.; Joulli , M. M. Total Synthesis

of Tamandarin B. Abstracts of Papers, 220th National Meeting of the

American Chemical Society, Washington, DC, 2000; ORGN 13.

POSTER PRESENTATIONS

Pierceall, W.E.; Carlson, N.; Richard, D. J.; Huang, X.; Elaschoff, M.;

Konopleva, M.; Kornblau, S.M.; Cardone, M.H.; Andreeff, M. BH3 profiling is

a predictive biomarker for response to cytarabine-based treatment of acute

myelogenous leukemia. American Society of Clinical Oncology Annual Meeting,

Chicago, IL, 2013.

Richard, D. J.; Carlson, N.; Pierceall, W.; Lena, R.; Bannister, T.;

Hodder, P.; Spicer, T.; Andreeff, M.; Opferman, J.; Koss, B.; Kung, A.;

Cardone, M. Characterization and development of on-target Mcl-1 inhibitors;

BH3 profiling provides a valuable drug discovery tool. Abstract 2466,

American Association for Cancer Research Annual Meeting, Washington, DC,

2013.

Richard, D. J.; Verheijen, J. C.; Curran, K.; Kaplan, J.; Brooijmans, N.;

Yu, K.; Toral-Barza, L.; Lucas, J.; Hollander, I.; Ayral-Kaloustian, S.;

Mansour, T.; Zask, A. Discovery of Dual Inhibitors of mTORC1 and mTORC2

with Excellent Kinase Selectivity. Gordon Research Conference on Medicinal

Chemistry, New London, NH, 2011.

CONFERENCES, MEETINGS, AND COURSES

2013 American Association for Cancer Research 104th

Annual Meeting

2011 Gordon Research Conference, Medicinal Chemistry

2010 American Chemical Society 32nd National Medicinal

Chemistry Symposium

2009 American Association for Cancer

Research "Chemistry in Cancer" Symposium

2008 American Association for Cancer Research 99th Annual

Meeting

2007 Drew University Medicinal Chemistry Course

2002 Gordon Research Conference, Natural Products

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