Design of Caspase Inhibitors as Potential Clinical Agents (Enzyme Inhibitors)

322 Pages·2008·12.82 MB·English

by  Tom O'Brien

Design of Caspase
Inhibitors as Potential
Clinical Agents
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CRC Enzyme Inhibitors Series
Series Editors
H. John Smith and Claire Simons
Cardiff University
Cardiff, UK
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Edited by Claudiu T. Supuran, Andrea Scozzafava and Janet Conway
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Edited by H. John Smith and Claire Simons
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CRC Enzyme Inhibitors Series
Design of Caspase
Inhibitors as Potential
Clinical Agents
Edited by
Tom O’Brien
Steven D. Linton
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CRC Press
Taylor & Francis Group
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Library of Congress Cataloging‑in‑Publication Data
Design of caspase inhibitors as potential clinical agents / editor(s), Tom O’Brien,
Steven D. Linton.
p. ; cm. ‑‑ (CRC enzyme inhibitors series)
Includes bibliographical references and index.
ISBN 978‑1‑4200‑4540‑6 (hardback : alk. paper)
1. Cysteine proteinases. 2. Cysteine proteinases‑‑Inhibitors. I. O’Brien, Tom. II.
Linton, Steven D. III. Series.
[DNLM: 1. Caspases‑‑antagonists & inhibitors. 2. Apoptosis. 3.
Caspases‑‑physiology. 4. Caspases‑‑therapeutic use. QU 136 D457 2009]
QP609.C94D47 2009
572’.76‑‑dc22 2008025506
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
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Contents
Preface......................................................................................................................vii
Editors.......................................................................................................................ix
Contributors .............................................................................................................xi
Chapter 1 Mammalian.Caspase.Activation.Pathways.in.Apoptosis.
and.Inflammation.................................................................................1
Susan E. Logue and Seamus J. Martin
Chapter 2 Role.of.Caspases.in.Inflammation-Driven.Diseases..........................19
Kristof Kersse, Tom Vanden Berghe, Saskia Lippens, Wim Declercq,
and Peter Vandenabeele
Chapter 3 Role.of.Caspases.in.Apoptotic-Driven.Indications............................59
Takashi Matsui
Chapter 4 Kinetics.and.Catalytic.Activity.of.Caspases......................................75
Kip A. Nalley
Chapter.5. Nonpeptide.Small.Molecule.Inhibitors.of.Caspases..........................93
Alexandre V. Ivachtchenko, Ilya Okun, Sergey E. Tkachenko,
Alex S. Kiselyov, Yan A. Ivanenkov, and Konstantin V. Balakin
Chapter 6 Identification.of.Inflammatory.Caspase.Inhibitors..........................123
John A. Wos and Thomas P. Demuth Jr.
Chapter 7 Identification.of.Apoptotic.Caspase.Inhibitors................................161
Brett R. Ullman
Chapter 8 Discovery.of.a.First-in-Class.Apoptotic.Caspase.Inhibitor.
Emricasan.(PF-03491390/IDN-6556)..............................................211
Niel C. Hoglen
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Chapter 9 Novel.Approaches.to.Caspase.Inhibitor.Discovery.........................225
Justin M. Scheer and Michael J. Romanowski
Chapter 10 Therapeutic.Potential.for.Caspase.Inhibitors:.
Present.and.Future...........................................................................251
Hiroyuki Eda
Index.......................................................................................................................289
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Preface
In.1992.the.first.report.was.published.describing.the.identification.of.caspase-1.or.
Interleukin-1β.Converting.Enzyme.(ICE),.the.founding.member.of.a.new.class.of.
cysteine.based.proteases..Since.then,.there.has.been.an.enormous.effort.to.discover.
small.molecule.inhibitors.of.this.therapeutically.important.class.of.enzymes..During.
this.period,.a.large.volume.of.literature.has.emerged.describing.the.identification.of.
a.diverse.range.of.inhibitors,.ranging.from.substrate-like.peptidic.to.non-peptidic.
heterocycles..Despite.this.significant.effort,.only.four.different.inhibitors.have.ini-
tiated.clinical.trials:.Pralnacasan.(VX740).for.rheumatoid.arthritis.(subsequently.
withdrawn.during.phase.II.trials);.VX765,.a.second.generation.caspase-1.inhibitor.
(entered.Phase.II.trials.for.psoriasis,.but.no.current.status.is.available);.Emricasan.
(PF-03491390/IDN-6556),.an.anti-fibrotic.agent..for.the.treatment.of..chronic.liver.
disease.(apparently.discontinued.after.completing.Phase.II.trials);.and.LB-84451,.for.
undisclosed.indications,.but.possibly.focusing.on.its.anti-fibrotic.activity.(currently.
in.Phase.II.trials)..This.emphasizes.the.difficulty.in.progressing.a.caspase.small.mol-
ecule.inhibitor.from.discovery.into.the.clinic,.and,.in.this.book,.we.intend.to.outline.
these.efforts.and.highlight.the.complex.issues.that.have.been.encountered...We.also.
will.present.the.current.status.of.clinical.trials.and.the.future.potential.for.caspase.
inhibitors.as.therapeutic.agents..
The.first.three.chapters.outline.what.is.currently.known.about.the.inflammatory.
and.apoptotic.caspase.pathways..Logue.and.Martin.(Chapter.1).present.a.comprehen-
sive.overview.of.the.key.caspase.proteolytic.pathways,.both.apoptotic.and.inflamma-
tory,.and.the.importance.of.these.pathways.in.normal.cellular.activities..Chapters.by.
Kersse.et..al..(Chapter.2).and.Matsui.(Chapter.3).provide.an.in-depth.coverage.of.the.
potential.therapeutic.value.of.an.inflammatory.or.apoptotic.(respectively).caspase.
inhibitor..In.each.of.these.chapters,.the.authors.present.an.overview.of.the.relevant.
pathways,.along.with.in vitro.and.in vivo.evidence.supporting.the.use.of.a.caspase.
inhibitor.for.each.indication..In.Chapter.4,.Nalley.reviews.the.catalytic.properties.
of.caspases,.how.to.use.these.properties.in.designing.inhibitors,.and.the.potential.
difficulties.involved.therein..In.particular,.one.of.the.key.outstanding.questions.in.
caspase.small.molecule.discovery.is.whether.a.specific.or.a.pan-caspase.inhibitor.
is.preferred..As.different.indications.will.likely.require.a.caspase.inhibitor.with.a.
unique.specificity.profile,.Nalley.illustrates.that.by.understanding.the.architecture.of.
each.caspase.active.site.and.its.known.substrate.specificities,.it.should.be.possible.to.
design.inhibitors.with.different.profiles..
We.then.turn.to.applying.this.knowledge.to.the.design.of.caspase.inhibitors.
and,.in.subsequent.chapters,.review.the.progress.already.made.toward.discovering.
small.molecule.inhibitors..Ivachtchenko.et.al.(Chapter.5).outline.progress.towards.
discovering.non-peptide.inhibitors.and.give.a.very.comprehensive.overview.span-
ning.a.large.number.of.different.chemical.classes..This.is.followed.by.a.chapter.by.
Wos.and.Demuth.(Chapter.6).that.summarizes.the.current.status.of.the.discovery.of.
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inflammatory.caspase.inhibitors.and.by.Ullman.(Chapter.7).that.gives.a.perspec-
tive.of.the.discovery.of.apoptotic.caspase.inhibitors..Chapter.8.presents.an.example.
of.the.preclinical.approach.undertaken.to.identify.an.apoptotic.caspase.inhibitor..
In.this.case,.Holgen.presents.a.case-study.of.the.discovery.and.characterization.of.
Emricasan,.a.compound.that.completed.Phase.II.clinical.trials,.but.is.now.reported.
as.discontinued.from.further.development..
As.described.in.the.previous.chapters,.caspase.inhibitors.have.been.predomi-
nantly.identified.either.by.functional.screens,.structure-based.design,.or.by.com-
putational.modeling..In.most.cases,.a.combination.of.all.three.approaches.has.been.
used..However,.as.new.technologies.have.emerged.so.have.the.approaches.taken.to.
inhibitor.discovery,.and.some.of.these.novel.approaches.are.presented.in.Chapter.9.
(Scheer.and.Romanowski)..The.advantage.of.using.novel.approaches.has.been.vali-
dated.by.the.discovery.of.an.allosteric.regulatory.site.that.lies.at.the.dimeric.inter-
face.between.the.caspase.large.and.small.subunits...The.presence.of.an.allosteric.
site.presents.an.opportunity.to.inhibit.catalytic.activity.that.avoids.the.limitations.
associated.with.designing.a.molecule.that.binds.to.the.active.site.
.In.the.final.chapter.(Chapter.10),.Eda.gives.an.overview.of.the.current.status.
of.ongoing.clinical.trials.with.caspase.inhibitors..A.survey.of.the.literature.indi-
cates.that.potent.caspase.inhibitors.can.be.discovered;.however,.advancing.these.
compounds.into.the.clinic.has.been.challenging..Some.of.the.key.issues.that.are.
discussed.revolve.around.questions.such.as.what.is.the.desired.selectivity.profile,.
whether.reversible.or.irreversible.inhibition.is.more.relevant.to.the.indication,.and.
what.impact.the.mode.of.inhibition.has.upon.the.toxicity.profile..The.answers.will.
likely.depend.upon.the.indication.being.pursued.and.whether.the.caspase.being.tar-
geted.is.apoptotic.or.inflammatory..
Despite.the.difficulties.involved.in.caspase.inhibitor.discovery,.considerable.
progress.has.been.made.and.early.clinical.studies.have.shown.promise..However,.of.
the.four.compounds.that.have.entered.clinical.trials,.two.have.been.discontinued.and.
the.fate.of.the.remaining.two.compounds.remains.unclear..Nevertheless,.the.poten-
tial.therapeutic.benefits.are.tremendous,.and.there.appears.to.be.a.renewed.enthu-
siasm.for.caspase.small.molecule.drug.discovery..If.one.of.the.current.compounds.
shows.clinical.benefit.and.makes.it.to.market.as.a.“first-in-class”.drug,.we.have.no.
doubt.that.this.will.fuel.an.enhanced.discovery.effort.for.additional.compounds.that.
could.be.“best-in.class.”.
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Editors
Dr. Steve Linton.has.been.involved.with.San.Diego.biotech.for.over.15.years,.not.
only.focusing.on.modulators.of.apoptosis.while.at.Idun,.but.also.working.in.several.
therapeutic.areas,.including.inflammation.and.oncology,.as.well.as.metabolic.and.
CNS.disorders..Dr..Linton.graduated.with.a.BS.degree.in.chemistry.from.Texas.
Christian.University.and.received.his.PhD.in.the.area.of.natural.product.synthesis.
from.Rice.University.under.the.direction.of.Dr..Tohru.Fukuyama..After.beginning.
his.medicinal.chemistry.career.at.Gensia.Pharmaceuticals.in.1992,.Dr..Linton.joined.
Idun.Pharmaceuticals.in.1995..He.contributed.to.the.development.of.Idun’s.caspase.
inhibitor.drug.discovery.platform.as.well.as.investigated.other.modulators.of.apop-
tosis.and.is.widely.published.in.this.area..Dr..Linton.was.promoted.to.medicinal.
chemistry.section.head.and.was.part.of.the.core.team.that.presented.Idun.technology.
to.potential.investors..Idun.was.acquired.by.Pfizer.in.2005,.and.its.flagship.caspase.
inhibitor,.Emricasan,.is.currently.in.late-stage.clinical.development..Dr..Linton.has.
also.participated.in.other.start-ups,.such.as.Synstar,.Inc.,.a.custom.synthesis.contract.
research.organization.(Hangzhou,.San.Diego),.as.well.as.Novasite.Pharmaceuticals,.
where.he.served.as.director.of.chemistry..He.is.currently.director.of.project.manage-
ment.at.Halozyme.Therapeutics.
Dr. Tom O’Brien.graduated.from.Trinity.College,.Dublin,.Ireland,.with.a.BA.(Mod).
degree.in.genetics..Dr..O’Brien.completed.his.PhD.degree.at.Cornell.University,.
Ithaca,.New.York,.in.the.laboratory.of.Dr..John.Lis,.and.subsequently.moved.to.
the.University.of.California.at.Berkeley.where.he.pursued.postdoctoral.research.
studies.in.the.laboratory.of.Dr..Robert.Tjian,.where.his.research.focused.on.dis-
secting.the.biochemical.and.molecular.regulation.of.eukaryotic.transcription..In.
1999.Dr..O’Brien.moved.to.the.newly.formed.company.Sunesis.Pharmaceuticals,.
where.his.work.focused.on.the.discovery.of.novel.small-molecule.caspase.inhibi-
tors..As.the.biology.project.leader.for.their.caspase.small-molecule.programs,.
Dr..O’Brien.was.one.of.the.key.people.that.helped.optimize.and.validate.their.frag-
ment-based.approaches.to.small-molecule.drug.discovery..During.his.time.at.Sune-
sis,.Dr..O’Brien.was.also.the.lead.biologist.for.a.number.of.additional.programs,.one.
of.which.recently.entered.clinical.trials..In.2006.Dr..O’Brien.joined.Genentech,.Inc.,.
in.their.newly.formed.Department.of.Cell.Regulation.
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