DNA-Encoded Libraries

280 Pages·2022·12.831 MB·English

by  Andreas Brunschweiger, Damian W. Young

Topics in Medicinal Chemistry 40
Andreas Brunschweiger
Damian W. Young   Editors
DNA-Encoded
Libraries
Topics in Medicinal Chemistry
Volume 40
SeriesEditors
PeterR.Bernstein,Philadelphia,PA,USA
AmandaL.Garner,AnnArbor,MI,USA
GundaI.Georg,Minneapolis,MN,USA
StefanLaufer,Tübingen,Germany
JohnA.Lowe,Stonington,CT,USA
NicholasA.Meanwell,Princeton,NJ,USA
AnilKumarSaxena,Kashipur,India
ClaudiuT.Supuran,SestoFiorentino,Italy
AoZhang,Shanghai,China
NuskaTschammer,Martinsried,Germany
Sally-AnnPoulsen,Nathan,Australia
Topics in Medicinal Chemistry (TMC) covers all relevant aspects of medicinal
chemistryresearch,e.g.pathobiochemistryofdiseases,identificationandvalidation
of (emerging) drug targets, structural biology, drugability of targets, drug design
approaches,chemogenomics,syntheticchemistryincludingcombinatorialmethods,
bioorganicchemistry,naturalcompounds,high-throughputscreening,pharmacolog-
ical in vitro and in vivo investigations, drug-receptor interactions on the molecular
level, structure-activity relationships, drug absorption, distribution, metabolism,
elimination, toxicology and pharmacogenomics. Drug research requires interdisci-
plinary team-work at the interface between chemistry, biology and medicine. To
fulfil this need, TMC is intended for researchers and experts working in academia
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expertise.
Medicinal chemistry is both science and art. The science of medicinal chemistry
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medicinal chemistry continues to challenge its practitioners with the need for both
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AllchaptersfromTopicsinMedicinalChemistryarepublishedOnlineFirstwithan
individualDOI.Inreferences,TopicsinMedicinalChemistryisabbreviatedasTop
MedChemandcitedasajournal.
(cid:129)
Andreas Brunschweiger Damian W. Young
Editors
DNA-Encoded Libraries
With contributions by
(cid:1) (cid:1) (cid:1)
M. J. Anderson A. Brunschweiger I. F. S. F. Castan
(cid:1) (cid:1) (cid:1) (cid:1)
E. Detta R. M. Franzini J. S. Graham Y. Gui
(cid:1) (cid:1) (cid:1) (cid:1)
H. Hassan T. Kodadek A. Lessing X. Li
(cid:1) (cid:1) (cid:1)
L. Marcaurelle J. I. Montgomery B. A. Morgan
(cid:1) (cid:1) (cid:1) (cid:1)
J. Odger C. L. A. Salvini A. Satz J. Scheuermann
(cid:1) (cid:1) (cid:1) (cid:1)
R. V. Stanton C. Taylor W. Tear M. J. Waring
(cid:1) (cid:1)
G. Yao Y. Zhang H. Zhu
Editors
AndreasBrunschweiger DamianW.Young
DepartmentofChemistryandChemical DepartmentofPharmacologyand
Biology ChemicalBiology,Departmentof
TUDortmundUniversity PathologyandImmunology,Center
Dortmund,Germany forDrugDiscovery
BaylorCollegeofMedicine
Houston,TX,USA
ISSN1862-2461 ISSN1862-247X (electronic)
TopicsinMedicinalChemistry
ISBN978-3-031-18628-8 ISBN978-3-031-18629-5 (eBook)
https://doi.org/10.1007/978-3-031-18629-5
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Preface
ThisbookonDNA-EncodedLibraries(DELs)comes30yearsaftertheideawasfirst
proposed by Lerner and Brenner. Their concept of encoding synthetic chemical
information with oligonucleotide sequences was initially viewed as more of an
academic curiosity. However, several influential publications that emerged in the
mid-2000silluminatedtheuniqueandpowerfuldrugdiscoverypotentialforDELs,
catapultingthetechnologyintoaspotlightthathasnotdiminishedsince.Thecurrent
DELlandscapeisvitalanditiscontinuingtoexpand.Todate,hundredsofresearch
papersonthetopicofDELtechnologyhavebeenpublished.Smallbiotechstolarge
pharmaceuticalcompaniesalikeareincreasinglyrelyingonDELsastheirprincipal
discoveryplatform.AcademicscientistsareenteringtheDELarenaatarapidpace,
bothasameanstosupplysmallmoleculesfortheirnewlyidentifieddiseasetargets
andasinnovatorstoDELtechnologyitself.Alloftheseaspectspointtothefactthat
DELtechnologyhasnowbecomeapillarintherapeuticdiscovery.
WebelievethatthetimingofthisTopicsinMedicinalChemistryvolumedevoted
toDNA-EncodedLibrariesisquiteappropriate.Booksofthistypeprovideboththe
bird’s-eyeviewandadetailedglimpseintotimeofagivenfieldandcanhavegreat
influence on its future direction. For example, A Handbook of DNA-Encoded
Libraries was published in 2014 and was a thoughtful compilation of information
relatedtothegeneraltechnologiesrequiredforthesynthesisandselectionofDELs.
This book undeniably contributed to the tremendous increase in DEL activity that
has been observed over the past 8 years and is responsible for bringing many
newcomerstothearea.However,theDELfieldhasmaturedconsiderablyoverthe
8yearssincetheHandbookofDNA-EncodedLibrarieswaspublished.Thegeneral
scientificareasthatDELwasbuiltaroundhavenowevolvedintofinelytunedDEL-
specificversions.InthisTopicsinMedicinalChemistryvolume,leaderswithinthe
DEL-field review these discrete areas of modern DEL science. We hope that the
assemblyofthesetopicswillcontinuetomotivatenewscientiststoutilizeDELsasa
discoveryengine.Atthesametime,webelievethatthisbookwillbehighlyrelevant
toexperiencedDELpractitionerswhomayhavelessfamiliaritywithsomecompo-
nentsoftheDELprocess.
v
vi Preface
Thechaptersthatcomprisethisvolumeareroughlyintendedtofollowtheflowof
the DEL pipeline from “concept to clinic.” The astrophysicist Carl Sagan said:
“Withoutunderstandingthepast you cannot understand thefuture.” Thus,Chap.1
byKodadekandSatzprovidesinsightintothepre-DELeradefinedbycombinatorial
chemistryandpre-DELbarcodingstrategiesforcombinatoriallibraries.Theydetail
someofthechallengesassociatedwithcombinatoriallibrariesthatprovidedamajor
drivingforcefortheconceptualizationofDELs.
The encoding of chemical information is the hallmark of DEL technology.
Encoding can be deployed in two basic ways: to solely record the synthesis infor-
mation or additionally as a means of driving the chemical reactions to produce the
encodedproducts.InChap.2,BrunschweigerandScheuermanndescribethevarious
encodingstrategiesthathavebeendevelopedforDELs.
SyntheticchemistryhasalwaysbeenafocalpointofDELtechnologygiventhat
the ability to generate large numbers ((cid:3)109) of structurally diverse compounds is
correlated to the capability to modulate a wide spectrum of biological targets.
However, thereactions usedto construct DELs areconstrained bythe requirement
formostlyaqueousconditionsandthepresenceofaDNAoligonucleotidewhichcan
diminish reaction efficiency. Rather than providing an exhaustive list of DEL-
compatible chemical reactions, which previous reviews have achieved, in Chap. 3,
Waringandcoworkersdescribethedevelopmentofgeneralchemicalplatformsand
mechanisticgenresthatcanenablethesynthesisofnovelDELswithhighfidelity
The preceding chapters on encoding strategies and DEL-chemical reactions
addressquestionssurroundinghowtoconstructDELsbutanequallyimportantset
ofquestionstoconsiderconcernwhichDELsshouldbemade.Basedontheanalysis
ofyearsofpreviousDELsynthesesandselectionoutcomes,inChap.4,Franziniand
ZhangturnalenstowardthegenerationofDELshavingmoredrug-likeproperties.
They point out that high-quality libraries are brought into existence based on
parameterized decisions around physicochemical properties of building blocks as
wellasconsiderationsoftheirstructuralfeatures.Thejudiciousselectionofchemical
reactionstoassemblethebuildingblocksisalsoanimportantaspect.
Computational science has long had an important role in chemistry and drug
discovery;however,DELsgenerateuniqueopportunitiesforcomputationaldeploy-
ment. In Chap. 5, Zhu et al. describe the various aspects of computational science
that have been applied to DEL technology within Pfizer. They point out how
cheminformaticscanenabletheselectionofappropriatebuildingblockstogenerate
thebestlibraryoutcomes.Furthermore,theyprovidedeepinsightintocomputational
workflows that allow for best practices for analyzing sequencing data from selec-
tionsleadingtohigh-qualityoff-DNAhits.
In the early development of DEL, there was a major emphasis on innovation in
the areas related to constructing the libraries (i.e., chemistry and encoding). While
concertedeffortscontinueintheseareas,recentyearshavebroughtaboutanincrease
in new technologies for selecting DELs against important targets. In Chap. 6, Gui
and Li review the topic of selection strategies. While classical DEL selection
strategieshavefocusedmainlyonbindingaffinity,newerstrategieswhichcanreveal
functionalbindershavenowemerged.
Preface vii
For therapeutic research, the ultimate measure of the utility of a new screening
platform is whether it leads to clinical candidates. In Chap. 7, Marcaurelle and
coworkers from GSK document the continuum in going from DEL selection to
clinicalcandidate.Whiletheprecedingchaptersinthisbookprovidedepthincritical
DEL-specific components, the chapter by Marcaurelle et al. ties all of the chapters
together to demonstrate the breadth and rigor that is required for clinical lead
development.TheydemonstratethatDELtechnologypassestheultimatetestlead-
ingtoclinicalcandidates.Moreover,theysuggestthattheassemblyoftechnologies
outlinedinthisbookarepoisedtogeneratescoresofnoveldrugsinthefuture.
Finally,giventhemanyimpressiveadvancementsoutlinedinthisbook,itwould
behardtoimaginethatDELtechnologyhasreachedaplateau.Thisisunderscored
bythelastchapterwhichisanaccountbyBarryMorganofHitGen.Morgan,akey
driver of DEL technology as it is widely practiced today, provides a historical
accountofthefieldandaperspectiveonwhereitmaygointhefuture.
In closing, this volume on Topics in Medicinal Chemistry on DNA-Encoded
Libraries is intended to encourage the application of DEL technology toward the
interrogation of new biological targets. Furthermore, the volume should serve to
identifyareaswherefurtherinnovationiswarrantedtowardincreasingtheefficiency
of DEL technology. The fulfillment of either of these objectives will undoubtably
leadtonewmedicinesfortreatinghumandisease.
Dortmund,Germany AndreasBrunschweiger
Houston,TX,USA DamianW.Young
August25,2022
Contents
AHistoryofSelection-BasedHigh-ThroughputScreeningTechnologies
forHitIdentification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ThomasKodadekandAlexanderSatz
BarcodingStrategiesfortheSynthesisofGeneticallyEncodedChemical
Libraries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
AliceLessing,ElenaDetta,JörgScheuermann,
andAndreasBrunschweiger
AdvancementsinDEL-CompatibleChemicalReactions. . . . . . . . . . . . . 65
MatthewJ.Anderson,IsalineF.S.F.Castan,JessicaS.Graham,
HaithamHassan,JakeOdger,CatherineL.A.Salvini,CameronTaylor,
andMichaelJ.Waring
DesignConsiderationsinConstructingandScreeningDNA-Encoded
Libraries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
YingZhangandRaphaelM.Franzini
CheminformaticsApproachesAidingtheDesignandSelection
ofDNA-EncodedLibraries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
HongyaoZhu,JustinI.Montgomery,andRobertV.Stanton
SelectionStrategiesinDNA-EncodedLibraries. . . . . . . . . . . . . . . . . . . 183
YuhanGuiandXiaoyuLi
FromDELSelectionstoValidatedHitstoClinicalLeads. . . . . . . . . . . . 217
LisaMarcaurelle,WestleyTear,andGangYao
APerspectiveon30YearsofDNA-EncodedChemistry. . . . . . . . . . . . . 259
BarryA.Morgan
ix
TopMedChem(2022)40:1–40
https://doi.org/10.1007/7355_2022_145
©TheAuthor(s),underexclusivelicensetoSpringerNatureSwitzerlandAG2022
Publishedonline:11October2022
A History of Selection-Based
High-Throughput Screening Technologies
fi
for Hit Identi cation
ThomasKodadekandAlexanderSatz
Contents
1 1990–1991:CombinatorialChemistry’s“BigBang”...................................... 2
2 ExploringEncodedLibraryStrategiesforSyntheticLibraries............................. 4
3 High-ThroughputParallelandCombinatorialSynthesis(WithoutEncoding)............. 5
4 WhatIsaHitMolecule?.................................................................... 6
5 RelationshipBetweenAssayandCompoundPurityRequirements....................... 7
6 TargetAgnosticLibraries................................................................... 9
7 FocusedLibraries............................................................................ 11
8 EncodingTechniques........................................................................ 13
9 SplitandPoolSolid-PhaseSynthesisofLibrariesofNon-peptidicOligomers........... 18
10 SummaryofPre-DELCombinatorialChemistryEfforts................................... 24
11 TheMaturationofGeneticallyEncodedLibraries......................................... 25
12 TargetAgnosticSolution-PhaseDECLs.................................................... 29
13 FocusedDECLs............................................................................. 30
14 Conclusion................................................................................... 31
References......................................................................................... 32
Abstract DNA-encoded libraries (DELs) are now used extensively in both aca-
demic and commercial laboratories for the discovery of protein ligands. DEL
technology is attractive because it allows very large compound libraries to be
screened at a low cost. In this chapter, we consider the origins of DELs in the
broaderpictureofcombinatorialchemistryandtracemanyimportantdevelopments
in the pre-DEL era that shaped current thinking in this area. The strengths and
weaknesses of traditional high-throughput screening (HTS), the previously domi-
nanttechnologyforhitfinding,areconsidered.Abriefhistoryofthedevelopmentof
bothencodedandnon-encodedcombinatoriallibrariesispresented,withaparticular
focusonthecriticalissueofthe“chemicalspace”coveredbythelibrariesmadein
T.Kodadek(*)
DepartmentofChemistry,UFScrippsBiomedicalResearch,Jupiter,FL,USA
e-mail:kodadek@ufl.edu
A.Satz
WuXiAppTec,WuXiHitS,Planegg,Germany