EliezerEliezer J. BarreiroJ. BarreiroProfessor Professor

INCTINCT--INOFAR, a Brazilian network forINOFAR, a Brazilian network for

drug design, discovery and developmentdrug design, discovery and developmentNationalNational InstituteInstitute ofof Science Science andand Technology in Technology in DrugsDrugs andand MedicinesMedicines

www.inctwww.inctwww.inctwww.inctwww.inctwww.inctwww.inctwww.inct--------inofar.ccs.ufrj.brinofar.ccs.ufrj.brinofar.ccs.ufrj.brinofar.ccs.ufrj.brinofar.ccs.ufrj.brinofar.ccs.ufrj.brinofar.ccs.ufrj.brinofar.ccs.ufrj.brINCT-INOFAR - Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde (CCS), UFRJ, Bloco K, 2º andar, Sala 23,

Cidade Universitária; PO Box: 68043, ZIP: 21944-971, Rio de Janeiro, R.J., Brazil

INCT-INOFAR - Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde (CCS), UFRJ, Bloco K, 2º andar, Sala 23,

Cidade Universitária; PO Box: 68043, ZIP: 21944-971, Rio de Janeiro, R.J., Brazil eliezer 2013

SummarySummary

��Prologue: a brief view of scientific research Prologue: a brief view of scientific research nowadays & nowadays & the the

interdisciplinarityinterdisciplinarity of complex of complex ddrug rug ddiscovery iscovery (DD) (DD) process;process;

��The pharmaceutical innovation and the role of the universityThe pharmaceutical innovation and the role of the university��The pharmaceutical innovation and the role of the universityThe pharmaceutical innovation and the role of the university

��The INCTThe INCT--INOFAR: INOFAR: our missionour mission

�� The INCTThe INCT--INOFAR: Who INOFAR: Who we are & what we are & what we dowe do

�� The INCTThe INCT--INOFAR: INOFAR: Final Final remarks remarks

�� AcknowledgmentsAcknowledgments

Galileo, Newton, Darwin, & Einstein

The scientific

research

through the

ages...

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Richard M. Ballew, Daniel H. Huson, Jennifer Russo Wortman, Qing Zhang, Chinnappa D. Kodira, Xiangqun

H. Zheng, Lin Chen, Marian Skupski, Gangadharan Subramanian, Paul D. Thomas, Jinghui Zhang, George L.

Gabor Miklos, Catherine Nelson, Samuel Broder, Andrew G. Clark, Joe Nadeau, Victor A. McKusick, Norton

Zinder, Arnold J. Levine, Richard J. Roberts, Mel Simon, Carolyn Slayman, Michael Hunkapiller, Randall

Bolanos, Arthur Delcher, Ian Dew, Daniel Fasulo, Michael Flanigan, Liliana Florea, Aaron Halpern, Sridhar

Hannenhalli, Saul Kravitz, Samuel Levy, Clark Mobarry, Knut Reinert, Karin Remington, Jane Abu-Threideh,

Ellen Beasley, Kendra Biddick, Vivien Bonazzi, Rhonda Brandon, Michele Cargill, Ishwar Chandramouliswaran,

Rosane Charlab, Kabir Chaturvedi, Zuoming Deng, Valentina Di Francesco, Patrick Dunn, Karen Eilbeck,

Carlos Evangelista, Andrei E. Gabrielian, Weiniu Gan, Wangmao Ge, Fangcheng Gong, Zhiping Gu,

Ping Guan, Thomas J. Heiman, Maureen E. Higgins, Rui-Ru Ji, Zhaoxi Ke, Karen A. Ketchum, Zhongwu Lai,

Yiding Lei, Zhenya Li, Jiayin Li, Yong Liang, Xiaoying Lin, Fu Lu, Gennady V. Merkulov, Natalia Milshina,

Helen M. Moore, Ashwinikumar K Naik, Vaibhav A. Narayan, Beena Neelam, Deborah Nusskern,

Douglas B. Rusch, Steven Salzberg, Wei Shao, Bixiong Shue, Jingtao Sun, Zhen Yuan Wang, Aihui Wang,

Xin Wang, Jian Wang, Ming-Hui Wei, Ron Wides, Chunlin Xiao, Chunhua Yan, Alison Yao, Jane Ye,

Ming Zhan, Weiqing Zhang, Hongyu Zhang, Qi Zhao, Liansheng Zheng, Fei Zhong, Wenyan Zhong,

Shiaoping C. Zhu, Shaying Zhao, Dennis Gilbert, Suzanna Baumhueter, Gene Spier, Christine Carter,

Anibal Cravchik, Trevor Woodage, Feroze Ali, Huijin An, Aderonke Awe, Danita Baldwin, Holly Baden,

Mary Barnstead, Ian Barrow, Karen Beeson, Dana Busam, Amy Carver, Angela Center, Ming Lai Cheng,

Liz Curry, Steve Danaher, Lionel Davenport, Raymond Desilets, Susanne Dietz, Kristina Dodson,Liz Curry, Steve Danaher, Lionel Davenport, Raymond Desilets, Susanne Dietz, Kristina Dodson,

Lisa Doup, Steven Ferriera, Neha Garg, Andres Gluecksmann, Brit Hart, Jason Haynes, Charles Haynes,

Cheryl Heiner, Suzanne Hladun, Damon Hostin, Jarrett Houck, Timothy Howland, Chinyere Ibegwam,

Jeffery Johnson, Francis Kalush, Lesley Kline, Shashi Koduru, Amy Love, Felecia Mann, David May,

Steven McCawley, Tina McIntosh, Ivy McMullen, Mee Moy, Linda Moy, Brian Murphy, Keith Nelson,

Cynthia Pfannkoch, Eric Pratts, Vinita Puri, Hina Qureshi, Matthew Reardon, Robert Rodriguez,

Yu-Hui Rogers, Deanna Romblad, Bob Ruhfel, Richard Scott, Cynthia Sitter, Michelle Smallwood,

Erin Stewart, Renee Strong, Ellen Suh, Reginald Thomas, Ni Ni Tint, Sukyee Tse, Claire Vech,

Gary Wang, Jeremy Wetter, Sherita Williams, Monica Williams, Sandra Windsor, Emily Winn-Deen,

Keriellen Wolfe, Jayshree Zaveri, Karena Zaveri, Josep F. Abril, Roderic Guigó, Michael J. Campbell,

Kimmen V. Sjolander, Brian Karlak, Anish Kejariwal, Huaiyu Mi, Betty Lazareva, Thomas Hatton,

Apurva Narechania, Karen Diemer, Anushya Muruganujan, Nan Guo, Shinji Sato, Vineet Bafna, Sorin Istrail,

Ross Lippert, Russell Schwartz, Brian Walenz, Shibu Yooseph, David Allen, Anand Basu, James Baxendale,

Louis Blick, Marcelo Caminha, John Carnes-Stine, Parris Caulk, Yen-Hui Chiang, My Coyne, Carl Dahlke, Anne Deslattes Mays,

Maria Dombroski, Michael Donnelly, Dale Ely, Shiva Esparham, Carl Fosler, Harold Gire, Stephen Glanowski, Kenneth Glasser, Anna Glodek,

Mark Gorokhov, Ken Graham, Barry Gropman, Michael Harris, Jeremy Heil, Scott Henderson, Jeffrey Hoover, Donald Jennings,

Catherine Jordan, James Jordan, John Kasha, Leonid Kagan, Cheryl Kraft, Alexander Levitsky, Mark Lewis, Xiangjun Liu, John Lopez,

Daniel Ma, William Majoros, Joe McDaniel, Sean Murphy, Matthew Newman, Trung Nguyen, Ngoc Nguyen, Marc Nodell, Sue Pan, Jim Peck,

Marshall Peterson, William Rowe, Robert Sanders, John Scott, Michael Simpson, Thomas Smith, Arlan Sprague, Timothy Stockwell, Russell Turner,

Eli Venter, Mei Wang, Meiyuan Wen, David Wu, Mitchell Wu, Ashley Xia, Ali Zandieh, and Xiaohong Zhu

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J. Whitfield, Nature 2008, 455, 720

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2011, 336, 3; R Guimera, B Uzzi, J Spiro, L A N Amaral, Team Assembly Mechanisms Determine

Collaboration Network Structure and Team Performance, Science 2005, 308, 697.

Technological innovation is a

process mostly dynamic in

industrial activity.

This dynamism is

accentuated in

pharmaceuticalpharmaceutical innovation pharmaceuticalpharmaceutical innovation

which, more than any other,

depend on the effective and

productive interaction

between

Science & Technology.

20112011

Why companies involved in DD fail than succeed at releasing the creative energy Why companies involved in DD fail than succeed at releasing the creative energy of its of its scientists? scientists?

MM AbouAbou--GharbiaGharbia,, WEWE Childers,Childers, DiscoveryDiscovery ofof InnovativeInnovative TherapeuticsTherapeutics:: Today’sToday’s RealitiesRealities andand Tomorrow’sTomorrow’s

VisionVision.. 11.. CriticismsCriticisms FacedFaced byby thethe PharmaceuticalPharmaceutical IndustryIndustry ,, JJ.. MedMed.. ChemChem.. 20132013,, 5656,, 56595659;; LJSLJS KnutsenKnutsen,,

DrugDrug discoverydiscovery management,management, smallsmall isis stillstill beautifulbeautiful:: WhyWhy aa numbernumber ofof companiescompanies getget itit wrongwrong,, DrugDrug

DiscovDiscov.. TodayToday 20112011,, 1616,, 476476..

New chemical entities 1993-2012

The The The The The The The The drugdrugdrugdrugdrugdrugdrugdrug world world world world world world world world marketmarketmarketmarketmarketmarketmarketmarket, in , in , in , in , in , in , in , in 2012 2012 2012 2012 2012 2012 2012 2012 = = = = = = = = cacacacacacacaca. . . . . . . . US$ US$ US$ US$ US$ US$ US$ US$ 895 895 895 895 895 895 895 895 bibibibibibibibi

“The productivity gap”“The productivity gap”

A. Mullard, 20122012 FDAFDA drugdrug approvals,approvals, Nature Rev. Drug Discov. 2013, 12, 87.

516516

J Hunter & S J Hunter & S StephensStephens, , NatureNature Rev. Rev. DrugDrug DiscovDiscov.. 20102010, , 99, 87, 87J Hunter & S J Hunter & S StephensStephens, , NatureNature Rev. Rev. DrugDrug DiscovDiscov.. 20102010, , 99, 87, 87

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DiscovDiscov.. 20112011,, 1010,, 321321;; FF PammolliPammolli etet alal..,, TheThe productivityproductivity crisiscrisis inin pharmaceuticalpharmaceutical R&DR&D,, NatureNature RevRev.. DrugDrug DiscovDiscov..

20112011,, 1010,, 428428 ;; MM Williams,Williams, ProductivityProductivity ShortfallsShortfalls inin DrugDrug DiscoveryDiscovery:: ContributionsContributions fromfrom thethe PreclinicalPreclinical Sciences?Sciences?

JPETJPET 20112011,, 336336,, 33;; SMSM PaulPaul etet alal..,, HowHow toto improveimprove R&DR&D productivityproductivity:: thethe pharmaceuticalpharmaceutical industry'sindustry's grandgrand challengechallenge,,

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DiscovDiscov.. 20092009,, 88,, 959959..

Innovation Innovation process process inin--househouse

= = ffully ully iintegrated ntegrated ppharmaceutical harmaceutical ccompanyompany

To To ffully ully iintegrated ntegrated ppharmaceutical harmaceutical nnetworketwork

InterInter--aliaalia: S : S LauferLaufer, U , U HolzgrabeHolzgrabe, D , D SteinhilberSteinhilber, , DrugDrug

ACS Med. Chem. Lett. ACS Med. Chem. Lett. 20132013, , 44, 313, 313

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EdEd. . 20132013, , 5252, 4072; A S , 4072; A S KesselheimKesselheim, J , J AvornAvorn, The , The

most transformative drugs of the past 25 years: a most transformative drugs of the past 25 years: a

survey of physicians, survey of physicians, Nature Rev. Drug Nature Rev. Drug DiscovDiscov. . 20132013, ,

1212, 425; H Wild, C , 425; H Wild, C HuweHuwe, M , M LesslLessl, , Collaborative Collaborative

InnovationInnovation —— Regaining the Edge in Drug Discovery,Regaining the Edge in Drug Discovery,

AngewAngew. Chem. Int. Ed. Chem. Int. Ed. . 20132013, , 5252, 2684; , 2684; W L W L JorgensenJorgensen, ,

Challenges for Academic Drug DiscoveryChallenges for Academic Drug Discovery,, Angew. Angew.

Chem. Int.Ed.Chem. Int.Ed. 20122012, , 5151,11680,11680; ; S Frye et al., US S Frye et al., US

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20112011, , 1010, 409; , 409; C J C J TralauTralau--Stewart et al., Stewart et al., Drug Drug

Discovery: New models for IndustryDiscovery: New models for Industry--Academic Academic

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sectorsector, , Future Med. ChemFuture Med. Chem. . 20092009, , 11, 1013., 1013.

The scientific manpowerThe scientific manpower

SourceSource: C. H. Brito Cruz & C. A. Pacheco, “Conhecimento & Inovação: Desafios do Brasil : C. H. Brito Cruz & C. A. Pacheco, “Conhecimento & Inovação: Desafios do Brasil no Século no Século XXI”, XXI”, atat

www.inovacao.unicamp.br/report/intcwww.inovacao.unicamp.br/report/intc--pachecopacheco--brito.pdfbrito.pdf (2009/01)(2009/01)

TheThe NationalNational InstitutesInstitutes ofof ScienceScience andand TechnologyTechnology (INCT’s)(INCT’s) programprogram

hashas ambitiousambitious andand largelarge goalsgoals inin termsterms ofof mobilizingmobilizing nationalnational efforteffort ofof

thethe bestbest researchresearch groupsgroups inin Brazil,Brazil, actingacting atat frontierfrontier andand strategicstrategic areasareas

ofof science,science, toto contributecontribute forfor sustainablesustainable developmentdevelopment ofof thethe countrycountry..

INCT-INOFAR

www.inctwww.inct--inofar.ccs.ufrj.brinofar.ccs.ufrj.br

GovernanceGovernance

committeecommittee

INCT-INOFAR

The TeamThe Team

INCT-INOFAR

Radical Radical InInovationovationRadical Radical InInovationovation

Discovery of novel Discovery of novel

anticancer drug anticancer drug anticancer drug anticancer drug

candidates designed as candidates designed as

novel novel combretastatincombretastatin

A4 analogues A4 analogues

LASSBioLASSBio--UFRJUFRJ / FM/ FM--UFCUFC

BR 10 2012 007619 5BR 10 2012 007619 5

PCT BR 2013 000095PCT BR 2013 000095

Study of the antiStudy of the anti--

inflammatory effect of inflammatory effect of

LASSBioLASSBio--897 on chronic 897 on chronic

lung diseases in mice lung diseases in mice

Laboratory of Laboratory of

Inflammation Inflammation

FIOCRUZ, RJFIOCRUZ, RJ

Antileishmanial activity of Antileishmanial activity of

new new NN--acylhydrazone acylhydrazone

derivatives and analogues derivatives and analogues

ICBICB--UFAL / LASSBioUFAL / LASSBio--UFRJUFRJ

Incremental Incremental InInnovationnovationIncremental Incremental InInnovationnovation

In Brazil the market ofIn Brazil the market of

ActActive pharmaceutical ingredients ive pharmaceutical ingredients

(API’s)

Generic drugsGeneric drugs*

"The art is to select [generics] that will be winners versus ones where there will be enormous competition.“

M McCoy, Generic Drugs, M McCoy, Generic Drugs, C&ENC&EN 20022002 (#13) (#13) 8080, 23, 23

In Brazil the market ofIn Brazil the market of

generic drugs isgeneric drugs is

caca. . 23,5% (2012)23,5% (2012)((BR BR LowLow # 9787, 02/10/1999) # 9787, 02/10/1999) > 92%

•• AtorvastatinAtorvastatin19911991

•• NewNew stereoselectivestereoselective synthesissynthesis byby

Professor Professor Luiz Carlos DiasLuiz Carlos Dias & &

DrDr Adriano S. VieiraAdriano S. Vieira, UNICAMP, SP , UNICAMP, SP

(2010) (2010) –– INPI INPI PatentPatent, 2011 (BR), 2011 (BR)

super blockbustersuper blockbustersuper blockbustersuper blockbustersuper blockbustersuper blockbustersuper blockbustersuper blockbuster––––––––drugdrugdrugdrugdrugdrugdrugdrug

IncrementalIncremental InInnovationnovationIncrementalIncremental InInnovationnovation

functionalized functionalized

pyrrolheptenoicpyrrolheptenoic acidacid

•• PatentPatent US 5273995 Pfizer (1991)US 5273995 Pfizer (1991)

LipitorLipitorTMTM

•• SunitinibSunitinib

World total sales: World total sales:

US$ > 120 bi US$ > 120 bi (1991(1991--2011)2011)

super blockbustersuper blockbustersuper blockbustersuper blockbustersuper blockbustersuper blockbustersuper blockbustersuper blockbuster––––––––drugdrugdrugdrugdrugdrugdrugdrug

**PatentPatent US 7211600 (2001) US 7211600 (2001)

•• SunitinibSunitinib20062006

SutentSutentTMTM••Multi TK Multi TK inhibitorinhibitor indicatedindicated to renal carcinoma to renal carcinoma

functionalizedfunctionalized

22--oxooxo--11HH--indol indol --11HH--pyrrolepyrrole--33--carboxamidecarboxamide

•• Total Total synthesissynthesis Professor Professor AngeloAngelo da Cunha da Cunha Pinto Pinto & Dra & Dra Bárbara Vasconcellos da SilvaBárbara Vasconcellos da SilvaUFRJ, RJ (UFRJ, RJ (20112011) (BR)) (BR)

Total sales of Total sales of tinibstinibs inin

US market: US$ 18,5 biUS market: US$ 18,5 bi

(2009)(2009)

AnnualAnnual ActivitiesActivities ReportReport

www.inctwww.inct--inofar.ccs.ufrj.br/download/aar/2012.pdfinofar.ccs.ufrj.br/download/aar/2012.pdf

Coordinator:Coordinator:

EliezerEliezer J. BarreiroJ. Barreiro

““For For allall thethe effortsefforts toto industrializeindustrialize andand

automateautomate discoverydiscovery,, historyhistory suggestssuggests

drugdrug discoverydiscovery is is artart

as as wellwell as as sciencescience andand reliesrelies heavilyheavily onon

FinalFinal remarksremarks

as as wellwell as as sciencescience andand reliesrelies heavilyheavily onon

thethe skillskill ofof experiencedexperienced drugdrug

huntershunters...“...“

Charles H. ReynoldsCharles H. Reynolds

Johnson & Johnson Pharmaceutical Research and Development, Spring House, PaJohnson & Johnson Pharmaceutical Research and Development, Spring House, Pa

em em Pharma'sPharma's Road AheadRoad Ahead ,, C&ENC&EN SpecialSpecial IssueIssue, , Volume 84, number 25, Volume 84, number 25, JuneJune 19, 200619, 2006

www.inct-inofar.ccs.ufrj.br

ThankThank youyou for for youryour attentionattention

AcknowledgmentsAcknowledgments

eliezer 2013