Rational Design of Small Molecules Targeting RNA

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Rational Design of Small Molecules Targeting RNA

Matt Disney

Department of Chemistry The Scripps Research Institute [email protected]

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Glossary of Terms • • • • • • • • •

RNA loops: non-canonically paired regions in RNA that are not base pairs (GC, AU, or GU). RNA secondary structure: a map of the base pairs and non-canonical pairs of an RNA. RNA secondary structure prediction: using free energy minimization to predict RNA structure, which can be further refined by using chemical probes such as DMS or SHAPE reagent. Two-dimensional combinatorial screening (2DCS): a library-versus-library screen to profile RNA and chemical space for binding partners. Inforna: a sequence-based rational design strategy for small molecules directed at RNA. Non-coding RNA: general term that describes RNAs that are synthesized in cells but do not encode for protein. microRNA: a non-coding RNA that is most typically a negative regulator of protein expression for a set of mRNAs. Chem-CLIP: Chemical Cross-Linking and Isolation by Pull Down, a method to determine the RNA targets of small molecules in cells. Chem-CLIP-Map: The Chem-CLIP method that determines or maps the binding sites of small molecules onto a given RNA transcript. 16

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“Lessons Learned” • Why do we care so much about “drugging” RNA in the postgenomic era? • What are known RNA targets of small molecules? • What are the challenges in exploiting human RNAs as targets for small molecules? • Can frameworks be developed to identify RNA folds that bind small molecules and small molecules that bind RNA folds? • How can one identify “druggable” RNA targets from sequence and lead compounds to “drug” them? • Can approaches to validate the RNA targets of small molecule be developed? • How can compounds be lead optimized to enhance potency and provide in vivo active compounds? 17

What are major challenges in developing small molecules targeting RNA? (possible multiple correct answers) • Selectivity: many RNAs can have similar folds. • Potency: there is little surface area for small molecules to interact with when an RNA does not have a complex 3D fold. • Biological activity: too few RNAs have important biological activity and are generally not important to target. • None of the above

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Drug Targets and the Proteome 3,050 (15%) Proteins in “Druggable” Protein Families

17,450 Proteins in “Un-druggable” Protein Families

Data from: PNAS (2007), 104, 19428 & Nature Reviews Drug Discovery (2002), 1, 727

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The Human Genome/Encode Projects – We “Drug” an Infinitesimal Amount of Our Genome!

Non -Transcribed DNA

“Non-Druggable” Proteome

”Druggable” Proteome Non-Coding RNA

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Exploited Drug Targets in the Transcriptome: Ribosome and Riboswitches

i#

ii#

iii#

5’#

Transcrip, on# iv# UUUUU#

NH3 -O

O

NH3

O

L"4"oxalysineNo#transcrip, on# UUUUU#

5’#

Inhibitor design, mimic substrate

NH3 -O

NH3 O

O

NH3

O

Lysine, natural substrate

Poehlsgaard J & Douthwaite S. Nat. Rev. Microbiol. 3, 870-881. Schuwirth BS, et al., & Cate JH. Science, 310, 827-34.

NH3

-O

L-4-oxalysine, substrate mimic, inhibitor

Blount KF, et al., & Breaker RR. Nat. Chem. Biol., 3, 44-9. Serganov A, Huang L, Patel DJ. Nature, 455, 263-7.

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A State-of-the-Art In Precision Therapeutics Towards RNA

An sense oligonucleo de Disease-Causing mRNA

An sense-Disease Causing mRNA Complex

Oligonucleotide Therapeutics: 1) Do not cross membranes/enter all tissues 2) Have non-specific effects 3) Ineffectively target structured RNAs 22

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Why are ribosomes attractive drug targets for small molecules? (possible multiple correct answers) • They are highly abundant • They serve an essential function in bacteria • They form complex three-dimensional folds like a protein • None of the above

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Disease-Causing RNAs Have Structures That Are Predictable From Sequence 5’UGGCCGAUUUUGGCACUAG CACAUUUUUGCUUGUGUCUC UCCGCUCUGAGCAAUCAUGU GCAGUGCCAAUAUGGGAAA3’

microRNA-96 Precursor, Oncogene

RNA Folding into Secondary Structure

UGGCCGAUUUUGGCACUA GCACAUUUUUGCUU GUGUCU AAAGGGUAUAACCGUGA CGUGUACU AACGAGUCU CGCCUC

Internal Loops

Bulges

Hairpin Loop

Prediction from sequence work of Turner, Tinoco, Zuker, Mathews, Weeks and others microRNA hairpin precursor secondary structures - miRBase

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Can RNA Bind Drugs Selectively? CU G GGC

CCG GUC

CGUG GUUC CACG

CG GC CCG

GACC CAAG GGAC

GCC

CU G GCC CUAG GUCC CGCG GAC

CC CAAG C G GGGC GAAC

CUCG GCCC

CG G GGC

CGUG CUUG GUCC GUUC GC CACG C G GAAC GACC CCAG CAGG GAAC

GGAC

CU G GUC

UUU AUA

CCCG GCCC

CGAG GUCC

CGCG GUCC

CGCG GGC

CAAG GAAC

GG CGGG C G GGGC GAAC

CGAG GAAC

CG GC CG G GCC

What do I like to bind? 25

Can RNA Bind Drugs Selectively? CU G GGC

CCG GUC

CGUG GUUC CACG

UG GC CCG

GACC CAAG GGAC

GCC

CU G GCC CUAG GUCC

CGCG GAC

CC CAAG C G GGGC GAAC

CUCG GCCC

CG G GGC

CGUG CUUG GUCC GUUC GC CACG C G G GAAC ACC CCAG CAGG GAAC GGAC

CU G GUC

UUU AUA

CCCG GCCC

CGAG GUCC

CGCG GUCC

CGCG GGC

CAAG GAAC

GG CGGG C G GGGC GAAC

CGAG GAAC

CG GC CG G GAC

… And many more 26

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Selection is Used to Populate an RNA Motif-Small Molecule Database Competitor Oligonucleotides can not be amplified by RT-PCR

A G C G C 5’

A A G C G

5’GGGAGA

RNA Motif Library, 4096 members

A G G 5’ C U A A U A N U N U N U U C A C A G U G U A U GCAAGG G G G 5’ GGGAGA

C A U U A A G G G U U U

A A G U A Selection of N binders N N A U Surface-Immobilized U Small Molecule G G A U C C GCAAGG

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Two-Dimensional Combinatorial Screening (2DCS) Probes RNA Motif and Small Molecule Libraries in Parallel N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

Cu(I)

+ Agarose-coated microarray

Small molecule library A#A# A#A# G# A# G# A# U#####C# C# G# C# G# U#####U# U#####U# G# C# A# U C# G# U# A# pre;miR;182# DM1# 5 # N N" Cancer# C2# C# A# N N" U# N N" A######A# G#####G# U U A# A# A# U HD&SCA3#FXS&FXTAS# A# A# U G# U G# G# # # # # # G# G# U G# G######G# G# U A# U G# U FTD#&#ALS# U G# C# Some%notable%% U G# C# # 5 GGGAGA# # GCAAGG# loops%in%3x3%ILL% 5 GGGAGA#

3x3#Internal# Loop#RNA# Library#(3x3#ILL)#

G#5 # U A# A# U U U C# C# G# G# A# GCAAGG#

C1#

Small molecule microarray Excise Binders, Sequence, & StARTS analysis

Hybridize with labeled 3x3 ILL

Small molecule microarray

2DCS: Disney MD, Labuda L.P., Paul DJ, Poplawski SG, Pushechnikov A, Tran T, Velagapudi SP, Wu M, Childs-Disney JL. J. Am. Chem. Soc. (2008), 130, 11185-94 and etc.

28

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Two-Dimensional Combinatorial Screening (2DCS) Probes RNA Motif and Small Molecule Libraries in Parallel N3

N3 N3 N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

N3

Cu(I)

+ Agarose-coated microarray Excision

Small molecule library A#A# A#A# G# A# G# A# U#####C# C# G# C# G# U# # # # # U# U#####U# G# C# A# U C# G# U# A# pre;miR;182# DM1# 5 # N N" Cancer# C2# C# A# N N" U# N N" A######A# G#####G# U U A# A# A# U HD&SCA3#FXS&FXTAS# A# A# U G# U G# G######G# G# U G# G######G# G# U A# U G# U FTD#&#ALS# U G# C# Some%notable%% U G# C# # 5 GGGAGA# # GCAAGG# loops%in%3x3%ILL% 5 GGGAGA#

3x3#Internal# Loop#RNA# Library#(3x3#ILL)#

of


Bound RNAs G#5 # U A# A# U U U C# C# G# G# A# GCAAGG#

Excise Binders, Sequence, & StARTS analysis

Hybridize with labeled 3x3 ILL


C1#

2DCS: Disney MD, Labuda L.P., Paul DJ, Poplawski SG, Pushechnikov A, Tran T, Velagapudi SP, Wu M, Childs-Disney JL. J. Am. Chem. Soc. (2008), 130, 11185-94 and etc.

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The Annotated RNA Motif-Small Molecule Database N N N

O

N H

N 3

1

U-A U U U-A

O N H

N

N H

N

N H

A-U C U U-A N H

O

O

2

N 3

O

HO HO

HN O NH2

HO O HO

O

3

U-A C C U-A

U U U U U-A

etc.

U-A C U U-A

A A U U G G

U-A G G A A

etc.

miR-96

N

N

G-U U C U-A

NH2

OH

NH2 OH

O OH

miR-515 miR-585 A-U U C U-A C A U U C U U U AU-AC A-U U U U-A DM2-Like DM2-Like ADAR site

Tightest Binding

Modest Binding

etc. No Binding

100% Fitness Velagapudi et al. Angew. Chem. Int. Ed. Engl., (2010), 49, 3816-3818.

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Life of a microRNA, global protein negative regulators Exportin 5 Dicer

pre-microRNAs

mature-miRNAs Drosha RNA Pol II

RISC

pri-microRNA

(A)N3’

(A)N 5’Cap mRNA-miRNA RISC Complex

5’Cap

Nucleus

Translational Repression

mRNA Cleavage

31

RNA Secondary Structures are: (possible multiple correct answers) • Impossible to predict from sequence • Not important. RNAs do not fold into defined structures. • Can define functional sites in an RNA for enzymatic modification and/or cleavage. • Potential binding sites for small molecules. • Able to define the evolutionary history of an organism and define the tree of life. 32

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Disney Group: General Approaches to Drug Structured RNAs with Small Molecules from Sequence

Database of RNA motif-small molecule interactions

infoRNA

Diseasecausing RNAs

Transcriptome-wide design of microRNA modulators: Velagapudi SP et al. Nat. Chem. Biol. (2014), 10, 291.

RNA secondary structures

No mature RNA

Small molecule inhibition (biogenesis, etc.)

Pro-apoptotic protein de-repressed Apoptosis in Breast Cancer 33

Disney Group: General Approaches to Drug Structured RNAs with Small Molecules from Sequence

Database of RNA motif-small molecule interactions

Liu B, Childs-Disney JL, Znosko BM, Wang D, Fallahi M, Gallo SM, Disney MD. infoRNA Analysis of secondary structural elements in human microRNA hairpin precursors. BMC Bioinformatics (2016), 17, 112. doi: 10.1186/s12859-016-0960-6. DiseaseDatabase of RNA Motifs in Human Non-Coding Small molecule inhibition RNA secondary causing (biogenesis, etc.) RNAs structures RNAs

Transcriptome-wide design of microRNA modulators: Velagapudi SP et al. Nat. Chem. Biol. (2014), 10, 291.

No mature RNA

Pro-apoptotic protein de-repressed Apoptosis in Breast Cancer 34

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Can Non-coding RNAs Be Drugged Selectively?

microRNA hairpin precursors Velagapudi SP et al. Nat. Chem. Biol. (2014), 10, 291.

35

Can Non-coding RNAs Be Drugged Selectively?

microRNA hairpin precursors Velagapudi SP et al. Nat. Chem. Biol. (2014), 10, 291.

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How selectively does 1 modulate the miR-96FOXO1 pathway and induce apoptosis? UGGCCGAUUUUGGCACUA GCACAUUUUUGCUU GUGUCU AAAGGGUAUAACCGUGA CGUGUACU AACGAGUCU CGC CUC

Norm. % TUNEL Positive Cells

1-pri-miR-96

100

(A)N

5’Cap

FOXO1 siRNA FOXO1 mRNA ablated

0

Compd. siRNA

-

1 -

1

1

apoptosis ?

37

Velagapudi SP et al. Nat. Chem. Biol. (2014), 10, 291.

1 Is at Least as Specific as a 23-mer Antagomir 1.E+03

Small molecule Antagomir, 23-mer

Treated Sample (2-DCt)

1.E+02 1.E+01 1.E+00 1.E-01

ac vate

1.E-02 1.E-03

miR-96

1.E-04

inhibit 1.E+03

1.E+02

Control Sample (2-DCt) Velagapudi SP et al. Nat. Chem. Biol. (2014), 10, 291.

1.E+01

1.E+00

1.E-01

1.E-02

1.E-03

1.E-04

1.E-05

1.E-05

38

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Can Non-coding RNAs Be Drugged Potently? UGGCCGAUUUUGGCACUA GCACAUUUUUGCUU GUGUCU AAAGGGUAUAACCGUGA CGUGUACU AACGAGUCU CGC CUC

inforna searching for “imperfect” binding to other sites UGGCCGAUUUUGGCACUA GCACAUUUUUGCUU GUGUCU AAAGGGUAUAACCGUGA CGUGUACU AACGAGUCU CGC CUC

1x1 GG Loop Binder

synthesis of designer dimers

UGGCCGAUUUUGGCACUA GCACAUUUUUGCUU GUGUCU GG UA AACCGUGA CGUGUA AACGAG AAA G U CU UCU CGC CUC

Targaprimir-96 Spacing Rules for multivalent ligands: Childs-Disney JL, Tsitovich PB, Disney MD. ChemBioChem, (2011), 12, 2143 Spacer alterations can improve uptake and localization: Lee MM, et al. Mol. Biosys., (2011), 7, 2441. Targaprimir-96: Velagapudi SP et al. PNAS, (2016), 113, 5898.

39

Can Non-coding RNAs Be Drugged Potently? UGGCCGAUUUUGGCACUA GCACAUUUUUGCUU GUGUCU GG UA AACCGUGA CGUGUA AACGAG AAA G U CU UCU CGC CUC

inforna searching for “imperfect” binding HN to other sites

NH

O

N

N

UGGCCGAUUUUGGCACU O A GCACAUUUUUGCUU GUGUCUN N CGUGUACU AACGAGUCU NCGC CUC N AAAGGGUAUAACCGUGA N

O

1x1 NGG Binder

H 2N Loop

O

O

N

O

N

2

HN synthesis N of designer H dimers

N N

UGGCCGAUUUUGGCACUA GCACAUUUUUGCUU GUGUCU GG UA AACCGUGA CGUGUA AACGAG AAA G U CU UCU CGC CUC

Targaprimir-96 Spacing Rules for multivalent ligands: Childs-Disney JL, Tsitovich PB, Disney MD. ChemBioChem, (2011), 12, 2143 Spacer alterations can improve uptake and localization: Lee MM, et al. Mol. Biosys., (2011), 7, 2441. Targaprimir-96: Velagapudi SP et al. PNAS, (2016), 113, 5898.

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1

*

100 80 60 40 20 0

Percentage of Cells in Early Apoptosis

Change in RNA Expression

1.7

50 nM

**

**

pr i-m pr iR-96 e- m i R96 mi R- 9 6 mi R- 1 m i 83 R- 1 82

0

Triple Nega ve *** Breast Cancer Cells MDA-231

Healthy Breast Cells

Targaprimir-96 Inhibits Biogenesis in Triple Negative Breast Cancer Cells and is Selectively Apoptotic

No Compd.

Velagapudi SP et al. PNAS, (2016), 113, 5898.

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Target Profiling Via Chemical-Cross Linking and Isolation by Pull Down (Chem-CLIP) Biotin purification module

Chem-CLIP Target Enrichment

Cl

N Cl

Cross-linking module

Target enrichment relative to cellular RNA

Chem-CLIP: Guan L, Disney MD. Angew. Chem. Int. Ed. Engl. (2013), 52, 10010. Chem-CLIP-Map: Yang WY, Wilson HD, Velagapudi SP, Disney MD. J. Am. Chem. Soc. (2015), 137, 5336. Applied to microRNAs: Velagapudi SP et al. PNAS, (2016), 113, 5898.

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Target Profiling Via Chemical-Cross Linking and Isolation by Pull Down (Chem-CLIP)

CompetitiveChem-CLIP (C-Chem-CLIP)

+

+

Target Depletion Relative to Chem-CLIP 43

Nucleic Acid Reactive Module

Cl

N Cl

Biotin Purification Module

Enrichment of pri-mir96 in Pull Down

Chemical-Cross Linking and Isolation by Pull Down (Chem-CLIP) *

6 3

**

0

Chem-CLIP Probe Chem-CLIP: Guan L, Disney MD. Angew. Chem. Int. Ed. Engl. (2013), 52, 10010. Chem-CLIP-Map: Yang WY, Wilson HD, Velagapudi SP, Disney MD. J. Am. Chem. Soc. (2015), 137, 5336. Applied to microRNAs: Velagapudi SP, et al. PNAS, (2016), 113, 5898.

+ 44

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Multivalent compounds have higher affinity and selectivity but: (possible multiple correct answers) • They are unlikely to penetrate tissues in vivo • They can be quickly excreted in vivo • They can be quickly metabolized in vivo • None of the above

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In vivo (MDA-MB-231) Activity of Targaprimir-96


46

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In vivo (MDA-MB-231) Activity of Targaprimir-96


47

“Lessons” Learned • Both RNAs with protein-like folds and ones with extensive secondary but limited tertiary structure can be targeted with small molecules • Strategies to identify selective interactions between small molecules and RNA motifs (2DCS) and tools to identify these targetable motifs in the transcriptome have been developed (Inforna) • Chem-CLIP and C-Chem-CLIP can validate the on- and offtargets of small molecules directed at RNA • Multivalency, enabled by Inforna, provides a robust approach to lead optimize small molecules targeting RNA for in vivo applications

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Thank you!

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•

•

•

•

•

• •

Partial Reference Slide RNA secondary structure prediction and annotation: (i) Mathews D., et al., Proc. Natl. Acad. Sci. U.S.A. (2004), 101, 7287; (ii) Zuker M, Nucleic Acids Res. (2003) 31, 3406. (iii) Siegfried N, et al. Nature Methods. (2014), 11, 959; (iv) Ding Y, et al. Nature (2014), 505, 696; (v) Rouskin S, et al. Nature (2014), 505, 701; (v) Wan Y, et al. Nature (2014), 505, 706. Reviews on RNA Targeting by Small Molecules: (i) Childs-Disney JL & Disney MD. Annual Review of Pharmacology and Toxicology, (2016), 56, 123-40; (ii) Bernat V & Disney MD. Neuron, (2015), 87, 2846; (iii) Guan L., ACS Chemical Biology, (2012), 7, 73-86; (iv) Velagapudi SP, et al. Current Opinion in Chemical Biology (2015), 24:97-103; (v) Thomas JR & Hergenrother PJ. Chemical Reviews, (2008), 108, 1171.; (vi) Chow CS & Bogdan FM. Chemical Reviews, (1997), 97, 1489–1514; (vii) Gallego J & Varani G. Accounts of Chemical Research, (2001), 34, 836; Connell CM, et al. Cell: Chemistry Biology, (2016), 23, 1077. Some salient and recent examples of small molecules targeting RNA identified by HTS: (i) Howe, et al. Nature (2015), 526, 672; (ii) Palacino, et al. Nature Chemical Biology (2015), 11, 511; (iii) Naryshkin, et al. Science (2014) 345, 688; (iv) Welch, et al. Nature (2007), 447, 87. HTS methods for microRNA RNA ligand discovery: (i) Haga, et al. ACS Chemical Biology, (2015), 10, 2267; (ii) Gumireddy, et al. Angew. Chem. Int. Ed. Engl. (2008), 47, 7482; (iii) Lorenz, et al. Bioconjugate Chemistry (2015), 26, 19. The Inforna design suite: (i) Velagapudi SP, et al. Nature Chemical Biology (2014), 10, 291; (ii) Disney MD, et al. ACS Chemical Biology. (2016), 11, 1720. available via license at http://disneylaboratory.com or https://disney.florida.scripps.edu RNA secondary structures in microRNA precusors: (i) miRBase.org; (ii) Liu B, et al. BMC Bioinformatics (2016), 17, 112. doi: 10.1186/s12859-016-0960-6. RNA repeating transcripts have also been actively drugged by small molecules: See work of, for 50 example, Zimmerman S, Miller B, Berglund A, & Disney MD.

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Rational Design of Small Molecules Targeting RNA

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