Bump-­‐and-­‐hole and PROTACs Alessio Ciulli School of Life Sciences, University of Dundee ELRIG Drug Discovery 2016, Liverpool 14th October 2016 TargeBng Protein-­‐Protein InteracBons (PPIs) with Chemical Probes Context and Vision Chemical probes to study biology and to aid therapeuBcs Drugs DNA CRISPR RNA RNAi Protein AnIbodies Chemical Probes Receptor ligands
Enzyme inhibitors
Nat. Rev. Drug Discov 2002, 1, 727
Drug Discov. Today 2005, 10, 1607
!
"
protein-protein
networks
protein-protein
complexes
#
challenging
targets
~1,000 Å2 Transcription factors
posttranslational
Regulatory complexes
modifications
Multisubunit enzymes
….
TargeBng Protein-­‐Protein InteracBons (PPIs) with Chemical Probes Context and Vision Chemical probes to study biology and to aid therapeuBcs Drugs DNA RNA Protein CRISPR RNAi AnIbodies Chemical Probes commentary
Nature America, Inc. All rights reserved.
The promise and peril of
chemical probes
Cheryl H Arrowsmith1,2, James E Audia3, Christopher Austin4, Jonathan Baell5, Jonathan Bennett6,
Julian Blagg7, Chas Bountra8, Paul E Brennan8,9, Peter J Brown1, Mark E Bunnage10, Carolyn Buser-Doepner11,
Robert M Campbell12, Adrian J Carter13, Philip Cohen14, Robert A Copeland15, Ben Cravatt16, Jayme L Dahlin17,
Dashyant Dhanak18, Aled M Edwards1*, Stephen V Frye19, Nathanael Gray20, Charles E Grimshaw21,
David Hepworth10, Trevor Howe22, Kilian V M Huber23, Jian Jin24–26, Stefan Knapp8,9, Joanne D Kotz27,
Ryan G Kruger28, Derek Lowe29, Mary M Mader12, Brian Marsden8, Anke Mueller-Fahrnow30,
Susanne Müller8,9, Ronan C O’Hagan31, John P Overington32,33, Dafydd R Owen10, Saul H Rosenberg34,
Brian Roth35, Ruth Ross36, Matthieu Schapira1,36, Stuart L Schreiber27, Brian Shoichet37, Michael Sundström38,39,
Giulio Superti-Furga23,40, Jack Taunton41,42, Leticia Toledo-Sherman43, Chris Walpole44, Michael A Walters45,
Timothy M Willson35,46, Paul Workman7, Robert N Young47 & William J Zuercher35,46
Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of
poor quality or that are used incorrectly generate misleading results. To help address these shortcomings,
we will create a community-driven wiki resource to improve quality and convey current best practice.
A
bout a decade ago, academia
substantially increased its efforts
in chemical biology and drug
discovery. These efforts arose in part
because of the availability of large numbers
of uncharacterized potential drug targets
emerging from genome sequencing efforts,
from the development and commoditization
of new screening technologies and
from the possibility of inventing new
medicines. Some of these efforts, perhaps
in appreciation of the complexity and
as powerful research tools and as seeds to
spur the development of new medicines
(Table 1).
Second, chemical reagents, akin to
any other protein-targeted reagent, are
only useful if they are potent, have known
selectivity and have a proven mechanism
of action. During the past decade, we have
gained a greater appreciation that probes
of this quality are difficult to produce and
require substantial resources, commitment
and skills. We learned that many of the
occurring artifacts in chemical screening
and chemical biology3,7 and countless
‘case-by-case’ papers describing the serious
deficiencies of specific chemical probes,
nonselective and/or poorly characterized
compounds continue to be widely used.
Thus, the evidence suggests that the
literature is an ineffective vehicle to provide
guidance to the community about the
quality of new chemical probes or to reduce
the use of low-quality chemical probes. We
argue that a complementary approach is
Nat. Chem. Biol. 2015, 11, 536
O
H
N
O
N
Adequate characterizaIon of chemical probes is paramount to aid reproducible results A major challenge lies in achieving target selecIvity and establishing on-­‐target acIvity Challenges to Chemical GeneBcs for EpigeneBcs •  Growing understanding of the links between epigeneIc effector proteins and disease 3. Probe selecBvity. Domains are clustered in large families with highly conserved binding sites 1. Complex phenotypic changes 2. Cell-­‐type, cell-­‐state dependent Runcie et al. Curr. Opin. Chem. Biol. 2016, 33, 186
Talk outline 1. Engineering selecBvity: Allele-­‐specific inhibiBon 2. Added layer of selecBvity: From inhibitors to degraders PROTAC
Ligand for
E3 ligase
VHL
Science, 2014, 346, 638
J. Med. Chem., 2016, 59, 1492
linker
BET
Bromodomain
Inhibitor
proteasome
ubiquitin
VHL$
E3$
Brd4$
Brd4$
ACS Chem. Biol., 2015, 10, 1770
Talk outline 1. Engineering selecBvity: Allele-­‐specific inhibiBon 2. Added layer of selecBvity: From inhibitors to degraders PROTAC
Ligand for
E3 ligase
VHL
Science, 2014, 346, 638
J. Med. Chem., 2016, 59, 1492
linker
BET
Bromodomain
Inhibitor
proteasome
ubiquitin
VHL$
E3$
Brd4$
Brd4$
ACS Chem. Biol., 2015, 10, 1770
BET bromodomain proteins and BET inhibitors Bromo and Extra-­‐Terminal (BET) proteins BRD2
BRD3
BRD4
BRDT
BD1
BD2
BD1
BD2
BD1
BD2
BD2
BD1
ET
ET
ET
ET
H4 pepIde Kac binding pocket BET bromodomain Structurally conserved ~ 110 aa in size BET bromodomain proteins and BET inhibitors Bromo and Extra-­‐Terminal (BET) proteins BRD2
BRD3
BRD4
BRDT
BD1
BD2
BD1
BD2
BD1
BD2
BD2
BD1
Target genes
TF
ET
RNA
Pol-II
ET
MYC
BCL2
….
ET
ET
Mediator
H4 pepIde BD1
PTef-β
BD2
N
ET
C
BRD4
Kac binding pocket BET bromodomain Structurally conserved ~ 110 aa in size BET transcripBonal co-­‐regulators, involved in many biological processes and linked to diseases including: Trends Biochem Sci, 2015, 40, 468 Cancer Nat Rev. Cancer 2012, 12, 465 Rare translocaIons e.g. BRD3 or BRD4 with NUT in NMC Cancer Genet Cyto. 2010, 203, 16 Obesity Nat Rev. Cancer 2012, 12, 465 InflammaIon J. Immunol. 2013, 190, 3670 Viral processes Cell 2014, 117, 349 amongst many others… BET bromodomain proteins and BET inhibitors Bromo and Extra-­‐Terminal (BET) proteins N
N
O
N
N
BRD2
BRD3
BRD4
BRDT
BD1
BD2
BD1
BD2
BD1
BD2
BD2
BD1
O
N
NH
O
N
S
ET
N
N
O
ET
ET
I-­‐BET762 Cl
ET
JQ1 Cl
Filippakopoulos et al., Nature 2010, 468, 1067-­‐1073; Nicodeme et al., Nature 2010, 468, 1119-­‐1123. H4 pepIde Pubmed%search%for%"JQ1"%or%"JQ81"%or%"I8BET"%or%
"BRD4"%or%"BET%bromodomains"%
180
No. of Publications
160
140
120
100
80
60
40
20
15
14
13
16
20
20
20
20
11
12
20
10
09
08
07
06
20
20
20
20
20
20
04
05
20
20
03
0
20
Kac binding pocket Year%of%Publica.on%
BET bromodomain Structurally conserved ~ 110 aa in size 10 BET inhibitors in 18 running trials (NMC, AML, ALL and other solid/hematological cancers) Nat Rev. Drug Discov. 2014, 13, 337 Nat. Biotechnol. 2016, 34, 361 LimitaIon of BET inhibitors: lack of intra-­‐BET selecIvity Target genes
Pan-BET
inhibitors
MYC
BCL2
….
BD1
BD2
N
ET
C
Pan-inhibition of
Brd2, Brd3 and Brd4
BET proteins
•  BET proteins and domains have different physiological roles (Shi & Vakoc, Mol. Cell. 2014) •  Genome occupancy paherns of BET proteins not idenIcal (Anders et al. Nat Biotech. 2014) •  TradiIonal geneIc techniques have proven challenging •  The pleotropic role of BET proteins have raised concerns about safety of BET inhibitors •  Need for selecBve targeBng of individual BET bromodomains A
GOAL: to engineer controlled selecIvity of BET bromodomain chemical probes Pan-selective probe inhibits multiple targets
B
Synthesis
Bump
Approach: Bump-­‐and-­‐Hole (Schreiber, Clackson, Shokat, Gray) Mutation
Hole
C
Mutant-selective probe inhibits single target
Runcie et al. Curr. Opin. Chem. Biol. 2016, 33, 186
A bump-and-hole approach to engineer controlled selectivity of
BET bromodomain inhibitors
Matthias
Baud
Enrique
Lin-Shiao
L/G, L/A
L/I
V/A
!
W/F
W/H
I-BET762 bound to Brd4-BD1
Baud, Lin-Shiao et al. Science, 2014, 346, 638
Baud, Lin-Shiao et al. J. Med. Chem., 2016, 59, 1492
A bump-and-hole approach to engineer controlled selectivity of
BET bromodomain inhibitors
Matthias
Baud
Enrique
Lin-Shiao
L/A
Baud, Lin-Shiao et al. Science, 2014, 346, 638
Baud, Lin-Shiao et al. J. Med. Chem., 2016, 59, 1492
Leu
BD*
Ala
L/A mutant
!
I-BET762 bound to Brd4-BD1
BD
• 
• 
• 
stable
retains histone binding and
Kac selectivity pattern
functionally silent
NN
N NOO
NN
N
OO
I
KHMDS
THF
-78 °C
10-56%
19-56%
NN
(+-)-IBET
O O
Cl
N O
N
O
N
O
ET shows 40–540 fold (average 160) overall selecBvity for L/A vs WT across the enBre BET subfamily * L/A mutants Cl
Wild-­‐types Cl
=
0"
ΔTm"/"degrees"C"
5"
10"
I-­‐BET762 iBET%
ME%
BD1"L/A"
ET%
O
BD1"WT"
BD2"WT"
N
N
O
N
N
BD2"L/A"
O
ET Cl
PR%
cPR%
Matt Baud, Enrique Lin-Shiao
ET vs L/A Kd = 85 nM ET vs WT Kd = 20 µM O
N
N
O
N
N
Cl
O
ET X-­‐ray crystal structures confirm “bump-­‐and-­‐hole” design raIonale Brd2(BD2) L383A mutant Co-­‐crystallized with ET bound 1.7 Å res. Baud, et al. Science, 2014, 346, 638
Cynthia
Tallant
SelecIvity of ET is validated in vitro within tandem BET bromodomain constructs Teresa
Cardote
WT/WT + iBET WT/WT + ET LA/WT + ET WT/LA + ET LA/LA + ET Baud, et al. Science, 2014, 346, 638
n Kd (nM) 1.8 360 n.d. >10,000 1.0 150 1.0 140 1.9 24 Fluorescence Recovery Aser Photobleaching (FRAP) in U2OS cell nuclei EGFP-Brd4
10 µm
bleach event WT/WT + DMSO!
WT/WT + 1µM iBET!
WT/WT + 1µM ET!
LA/WT + 1µM ET!
WT/LA + 1µM ET!
LA/LA + 1µM ET!
Annica
Pschibul
t = 1.5s t = 3.2s •  TargeIng BD1 is sufficient to displace Brd4 from chromaIn 4!
n.s. * *** *** 3!
*** 2!
t = 15.4s t1/2 (seconds)!
pre-­‐bleach 1!
LA/WT WT/LA LA/LA WT/WT ET I-­‐BET ET DMSO 1 µM 1 µM 1 µM BD1
0!
N
ET
BD2
C
A revised model
Baud, et al. Science, 2014, 346, 638
Summary – Part 1 ‘Bumping’ selecIvity onto BET inhibitors • 
• 
• 
• 
Developed and opImized bump-­‐and-­‐hole vs a PPI target Developed new syntheIc routes to triazolo-­‐BZP analogues Applied the approach to dissect the role of individual PPIs Extension to other bromodomains / epigeneIc reader families warranted •  New tool for enhanced validaIon of BET proteins as targets N
N
N
O
S
N
O
A single Target
is inhibited
Cl
Selective Target inhibition
Talk outline 1. Engineering selecBvity: Allele-­‐specific inhibiBon 2. Added layer of selecBvity: From inhibitors to degraders PROTAC
Ligand for
E3 ligase
VHL
Science, 2014, 346, 638
J. Med. Chem., 2016, 59, 1492
linker
BET
Bromodomain
Inhibitor
proteasome
ubiquitin
VHL$
E3$
Brd4$
Brd4$
ACS Chem. Biol., 2015, 10, 1770
Natural pathway S Ub Ub Ub proteasome E2 SRS
r to
Adap
RING Cullin S = Substrate SRS = Substrate RecogniIon Subunit = Post-­‐translaIonal modificaIon Cullin RING E3 ligases (>200 in humans; up to 20% of proteasome-­‐dependent degradaIon can be CRL-­‐dependent) (Deshaies, PavleIch, Zheng, Schulman, Peters, Bullock et al.) Natural pathway S Ub Ub Ub Ub proteasome E2 SRS
tor
Adap
RING Cullin S = Substrate SRS = Substrate RecogniIon Subunit = Post-­‐translaIonal modificaIon Cullin RING E3 ligases (>200 in humans; up to 20% of proteasome-­‐dependent degradaIon can be CRL-­‐dependent) (Deshaies, PavleIch, Zheng, Schulman, Peters, Bullock et al.) Natural pathway proteasome E2 SRS
tor
Adap
RING Cullin Proteolysis TargeIng Chimeras (PROTACs) (Crews, Deshaies, Sakamoto) Ligand for E3
Ligand for
Target
Linker
Target Ub Ub Ub E2 RING SRS r to
Adap
Cullin Natural pathway proteasome E2 SRS
RING Cullin tor
Adap
Proteolysis TargeIng Chimeras (PROTACs) 2nd generation PROTAC.2
b)
Ligand for E3
Ligand for
Target
Linker
AR
ligand
Target Ub Ub Ub H
poly-Arg tag
HN
H
ALA(Hyp)YIP-(D-Arg)8
O
E2 RING SRS r O
H
Ub NH
O
to
Adap
(Crews, Deshaies, Sakamoto) O
H
Cullin heptapeptide
HIF-1α motif
O
(2001-­‐2005) Design and optimization of VHL ligands
(2010-2014)
Dennis Buckley
(Yale)
J. Am. Chem. Soc. 2012 134, 4465
Chem. Biol. 2012 19, 1300
Angew. Chem. Int. Ed. 2012 51, 11463
Inge David
van Molle
Dias
(Cambridge)
ACS Med. Chem. Lett. 2014, 5, 23
J. Med. Chem. 2014, 57, 8657
unpublished
Kd (µM) LE
5.0
0.24
1.0
0.26
0.18
0.04
0.28
0.28
Hif-1α peptide
bound to VHL
!
capped-Hyp
Structure-based design
>60 ligand-bound structures
OH
S
OH
O
N
Group
Efficiency
N
H
N
O O
N
H
O
O
NH
LHS Hyp RHS1 RHS2
•  Initiated collaboratively with the Crews Lab (2010-12)
•  Led to founding of GSK DPU and Arvinas (2013)
N
O
VH032 N
1"
0"
N
O
Kd = 180 nM NHA = 33; MW = 472 Da LogD7.4 = 0.62; cLogP = 1.7 Morgan
Carles
Gadd
Galdeano
(Dundee)
Galdeano et al. J. Med. Chem, 2014, 57, 8657
(top most read arBcle in J. Med. Chem. for 2015)
VHL Cul2 E3 ubiquitin ligase and hypoxic signalling
OH
PHD inhibitors
IOX-2, FG-4592
S
N
O
N
H
O
NH
O
VHL inhibitors
HRE EPO
N
VHL Cul2 E3 ubiquitin ligase and hypoxic signalling
OH
PHD inhibitors
IOX-2, FG-4592
S
N
O
N
H
O
NH
O
VHL inhibitors
HRE EPO
N
Discovery of VH298, a potent and selecIve VHL inhibitor as chemical probe of the hypoxic signalling pathway OH
Time (min)
S
N
O
NC
NH
O
0
NH
N
10
20
30
40
0.00
O
Carles
Galdeano
CollaboraIon with Sonia Rocha, Doreen Cantrell, Kevin Read (SLS Dundee) and Paola Grandi (Cellzome-­‐GSK) Frost et al., Nature Comm. In Press ITC
-0.50
0.0
kcal mol of injectant
-1
50
-8
Morgan
Gadd
-0.30
-0.40
0
Pedro
Soares
-0.20
Kd = 80 nM 100
% D is p la c e m e n t
Julianty
Frost
FP
µcal/sec
-0.10
VH298
-7
-6
-5
-2.0
-4.0
AcIve trans InacIve cis -6.0
-4
0.0
lo g [ V H L in h ib it o r s ]
0.5
1.0
Molar Ratio
SPR
X-ray
koff = 0.065 s-1 VH298
1.5
2.0
Discovery of VH298, a potent and selecIve VHL inhibitor as chemical probe of the hypoxic signalling pathway proteasome inhibitor
HeLa 2 hr VH298 (µM)
PHD inhibitors
(100 µM)
250
148
HIF-1α (low)
98
250
148
HIF-1α (high)
98
250
148
98
50
Frost et al., Nature Comm. In Press HIF-1α-OH
β-actin
Discovery of VH298, a potent and selecIve VHL inhibitor as chemical probe of the hypoxic signalling pathway HIF-target genes
CTLs – GLUT1 VH032 VH298 cis-­‐VH032 cis-­‐VH298 RelaBve EPO mRNA levels in RCC4 cells RelaBve mRNA levels 5 RCC4 – EPO producBon 4.5 4 3.5 3 2.5 2 1.5 1 0 50 100 150 200 ConcentraBon (µM) Frost et al., Nature Comm. In Press 250 3.50 DMSO VH298 * 3.00 2.50 2.00 1.50 1.00 0.50 0.00 HA HA-­‐VHL Discovery of VH298, a potent and selecIve VHL inhibitor as chemical probe of the hypoxic signalling pathway HIF-target proteins
HFF 24 hr; 100 µM 148
HIF-1α
98
148
HIF-2α
98
64
64
CA9
GLUT1
50
50
Frost et al., Nature Comm. In Press β-actin
Discovery of MZ1, a selective Brd4 degrader
Michael
Zengerle
Kwok-Ho
Chan
JQ1
MZ1
PROTAC
Ligand for
E3 ligase
VHL
linker
BET
Bromodomain
Inhibitor
proteasome
ubiquitin
VHL$
E3$
Brd4$
Brd4$
Zengerle et al, ACS Chem Biol, 2015, 10, 1770
VHL ligand
Discovery of MZ1, a selective Brd4 degrader
Michael
Zengerle
MZ1
MZ1 retained binding affinities of JQ1 and
VH032 for BET-brd and VHL, respectively
EGFP-Brd4
MZ1 Brd4
Kwok-Ho
Chan
Brd3
Brd2
EGFP-Brd4
β-Actin
siRNA (48h)
Compound
(1 µM, 24h)
mock
Brd2
Brd3
cisMZ1 Brd4
cisMZ1
vehicle
MZ1
JQ1
vehicle
U2OS, 4h treatment Zengerle et al, ACS Chem Biol, 2015, 10, 1770
Discovery of MZ1, a selective Brd4 degrader
DMSO MZ1 (24 hr) 10 µM 100 nM MZ1 BRD4 Brd4
BRD3 Brd3
BRD2 Brd2
β-­‐AcIn β-Actin
0 4 8 12 16 24 36 (h) MZ1 preferenIally degrades Brd4 over Brd2 and Brd3 •  MZ1 affects fewer genes compared to JQ1 in cancer cells, consistent with selective
Brd4 knockdown
Zengerle et al, ACS Chem Biol, 2015, 10, 1770
MZ1 treatment
(1 µM) wash
Brd4 long
Brd4 short
Brd3
Brd2
β-Actin
0
4
8
12
24
36
48 (h)
Protein level recovered only 20 h aser compound wash: requires re-­‐synthesis Zengerle et al, ACS Chem Biol, 2015, 10, 1770
OH
N
N
O
H
N
N
S
N
O
N
O
O
N
H
O
O
N
H
O
N
S
JQ1
VHL-binding moiety
MZ1
Cl
Zengerle et al. ACS Chem. Biol. 2015
H
N
HN
N N
O
N
O
O
O
N
NH
O
S
JQ1
O
N
O
dBET1
Winter, Buckley et al. Science 2015
Cl
CRBN-binding moieties
O
O
O
O
HN
NH
N N
O
N
O
N
O
N
NH
O
S
O
ARV-825
Lu et al. Chem. Biol. 2015
Cl
JQ1
OH
O
S O
NH
S
O
N
O
N
O
4
N
N
H
O
O
N
H
N
S
VHL-binding moiety
PROTAC_RIPK2
Bondeson et al. Nat. Chem. Biol. 2015
OH
N
N
O
H
N
N
S
N
O
N
O
O
N
H
O
O
N
H
O
N
S
JQ1
VHL-binding moiety
MZ1
Cl
Zengerle et al. ACS Chem. Biol. 2015
H
N
HN
N N
O
N
O
O
O
N
NH
O
S
JQ1
O
N
O
dBET1
Winter, Buckley et al. Science 2015
Cl
CRBN-binding moieties
O
O
O
O
HN
NH
N N
O
N
N
O
N
NH
O
S
“... the sky is the limit for PROTACs” Nat Chem Biol. 2015 Aug 18; 11:634-­‐5 O
O
ARV-825
Lu et al. Chem. Biol. 2015
Cl
JQ1
OH
O
S O
NH
S
O
N
O
N
O
4
N
N
H
O
O
N
H
N
S
VHL-binding moiety
PROTAC_RIPK2
Bondeson et al. Nat. Chem. Biol. 2015
OH
N
N
O
H
N
N
S
N
O
N
O
O
N
H
O
O
N
H
O
N
S
JQ1
VHL-binding moiety
MZ1
Cl
Zengerle et al. ACS Chem. Biol. 2015
H
N
HN
N N
O
N
O
O
O
N
NH
O
S
JQ1
O
N
O
dBET1
Winter, Buckley et al. Science 2015
Cl
CRBN-binding moieties
O
Press Release
O
O
O
HN
NH
N N
O
N
N
NH
O
Press Release
th
EMBARGOED: 14 July 2016, 10am (BST)
Boehringer Ingelheim and University
of Dundee collaborate to develop new
class of medicines
Collaboration aims to develop PROteolysis TArgeting
Chimeric molecules (PROTACs) – a new therapeutic
modality that is able to degrade proteins playing a central
role in disease processes
PROTACs and their new mechanism of action are expected
to open new horizons for drug development allowing new
drug targets to be accessible
Research bears potential to develop innovative new
treatment options for patients with high medical need
Ellesfield Avenue
Bracknell, Berkshire
United Kingdom
RG12 8YS
Phone: +44 (0)1344 741155
Email: [email protected]
ISDN: +44 (0)1344 311104
O
ARV-825
Lu et al. Chem. Biol. 2015
Cl
JQ1
OH
O
Contact:
Boehringer Ingelheim Limited
Communications
O
N
S
For UKttrade
medical
“... he s&ky is tmedia
he lonly
imit for PROTACs” Nat Chem Biol. 2015 Aug 18; 11:634-­‐5 O
S O
NH
S
O
N
O
N
O
4
N
N
H
O
O
N
H
N
S
VHL-binding moiety
PROTAC_RIPK2
Bondeson et al. Nat. Chem. Biol. 2015
Outlook 1) inhibitor:
N
N
O
N
S
N
O
Several Targets
are inhibited
JQ1
Pan-inhibition
Cl
N
2) Bump and hole:
N
N
O
S
N
O
A single Target
is inhibited
ET
Cl
Ad hoc selective inhibition
3) PROTAC:
OH
N
O
N
H
N
N
S
N
O
O
O
O
N
N
H
O
O
S
N
H
N
MZ1
Cl
A single Target
is depleted
Selective Target degradation
Summary – Part 2 Turning inhibitors into selecIve degraders •  ConjugaIng JQ1 to a VHL ligands yields PROTACs that induce preferenIal degradaIon of Brd4 leaving Brd2 and Brd3 untouched •  MZ1 shows improvements over BET inhibitors as chemical probe and therapeuIc lead •  Provides proof-­‐of-­‐concept for turning non-­‐selecIve ligands into more selecIve degraders •  Opportunity to validate the therapeuIc potenIal of degrading proteins using small molecules PROTAC
A single Target
is depleted
Selective Target degradation
Ciulli Laboratory Current members Anastasia Amato Alessio Bortoluzzi Elvira Bruno Teresa Cardote Guilherme Castro Kwok-­‐Ho Chan Morgan Gadd Scoh Hughes Julianty Julianty Xavier Lucas Chiara Maniaci Ester Morreale Andrew Runcie Pedro Soares Andrea Testa Wei-­‐Wei-­‐Kung Funding Collaborators SGC Oxford: Stefan Knapp and colleagues at SGC Oxford Yale University: Craig Crews, Dennis Buckley and colleagues at Yale Cellzome: Paola Grandi, Marcus Batscheff and colleagues at Cellzome Dundee SLS: Dario Alessi, Doreen Cantrell, Axel Knebel, Kevin Read, Sonia Rocha, Helen Walden, DDU and colleagues Former members Ma}a Cocco Michael Zengerle Carles Galdeano Mahhias Baud Enrique Lian-­‐Shiao Cynthia Tallant Annica Pschibul Jordi Rosello Lars van Beurden Inge Van Molle David Dias Emil Bulatov Fleur Ferguson Terence Kwan Charlohe Sutherell Mahhew Smith Sarah Hewih Lois Overvoorde Jemima Thomas Kyle Smith Ernie So