John Pollard Ph.D
1
© 2013
Vertex
Pharmaceuticals
Incorporated | VXR-EU-ONC-00003 | 09/2013
©2012
Vertex
Pharmaceuticals
Incorporated
Discovery
and characterisation of
Title Placeholder
potent
and selective inhibitors of ATR
Name | Date
kinase as anti-cancer agents
Damage to our DNA is relentless
U to
Up
t 1 million
illi d
damage events
t per cellll per d
day
Cell
M t b li
Metabolism
Repair
2
Viral
Infection
Radiation
Cell death
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Drugs
Senescence
Replication
Errors
Mutation
Damage to our DNA is relentless
U to
Up
t 1 million
illi d
damage events
t per cellll per d
day
Cell
M t b li
Metabolism
Repair
Viral
Infection
Radiation
Cell death
Drugs
Senescence
Replication
Errors
Mutation
• Many standard-of-care anti-cancer drugs work by inducing DNA damage ….
…. BUT don’t
don t work well because the damage gets repaired
3
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Complex surveillance and repair network in place
Single strand defects
Metabolic
biproducts
IR,
Alkylating agents
Replication errors
DR
BER
MMR
(eg A-G or T-C mismatch)
Double strand breaks
UV light
NER
IR, DSB agents
(topo II inhibitors)
NHEJ
Replication
stress, IR
HR
Blocking DNA repair processes will increase toxicity of DNA damage
– challenge is to make this specific for cancer cells
44
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Defective DNA damage repair can improve
responses to therapy
• NSCLC patients stratified on the basis of ERCC1 status1
• Testicular cancer has a high response rate to platinum based therapy (>90%
cure)2
• Attributed to defects in repair including ERCC1
1Modified
5
from New Eng. J.Med. (2006) 355, 983
2PNAS
(2002) 99, 4592
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Complex surveillance and repair network in place
Single strand defects
66
Metabolic
biproducts
IR,
Alkylating agents
Replication errors
DR
BER
MMR
(eg A-G or T-C mismatch)
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Double strand breaks
UV light
NER
IR, DSB agents
(topo II inhibitors)
NHEJ
Replication
stress, IR
HR
Unperturbed replication fork
ssDNA-binding
Lagging strand
protein
Helicase
G2
M
Cell
cycle
S
G1
Replication fork
movement
Leading strand
7
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Unperturbed replication fork
DNA damage
event
M
ssDNA-binding
Lagging strand
protein
Helicase
G2
Cell
cycle
S
G1
Replication fork
movement
Leading strand
8
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Unresolved damage persists to S-phase
G2
M
Cell
cycle
S
DNA
damage
ssDNA-binding
Lagging strand
protein
Helicase
G1
Replication fork
movement
Leading strand
9
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Replication fork encounters damage lesion
ssDNA-binding
protein
p
ote
Lagging strand
Helicase
Leading strand
Replication fork
movementt
10
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Replication fork stalls – Replication stress
Uncoupled single stranded DNA is exposed
ssDNA-binding
protein
p
ote
Lagging strand
Helicase
Leading strand
Replication fork
movementt
11
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
ATR kinase is recruited to stalled fork
Arrests replication, controls origin firing and directs repair
ssDNA-binding
protein
p
ote
Lagging strand
Helicase
Leading strand
ATR
Replication fork
movementt
ATRIP
ATR
ATRIP
ATR
ATRIP
ATR
ATRIP
12
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
ATR
ATRIP
Without ATR stalled replication fork collapses
Forms a double strand break
ssDNA-binding
protein
p
ote
Lagging strand
Helicase
Leading strand
Replication fork
movementt
Double Strand Break (DSB)
13
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Extensive overlap between replication stress and DSB
repair
i pathways
th
DNA damage response (DDR)
Direct DSB
Replication stress
Intrinsic reactive oxygen species
IR, topoisomerase inhibitors
Intrinsic replication errors
Unresolved DNA damage
(from treatment with any DNA damaging agents)
ATM
ATR
Replication fork
(during S-phase)
Fork
collapse
Repair
Hundreds of shared substrates
Cell cycle arrest
Repair
Replication control
(primarily HR)
Modified from Jackson SP, Bartek J. Nature. 2009;461(1071):1071-1078. DOI: 10.1038/nature08467.
14
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Survival
Many cancer cells appear to be reliant on ATR
• Frequent defects in overlapping repair pathways
• p53, MRN, ATM
• High background replicative stress
• Defects in G1 checkpoint, expression of oncogenes such as kRas, hypoxia
Replicative stress
ATR
ATM
Chk1
Chk2
Survival
15
DSB
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
p53
53
Discovery
y of ATR inhibitors
• High throughput screen of in
in-house
house library of kinase focused compounds
– Biochemistry kinase screen using recombinant ATR
• ATP competitive mechanism of action
• Moderate ATR potency
– Ki 0
0.31µM
31µM
• Encouraging selectivity
– Ki ATM >4µM
µ
– Ki DNA-PK >4µM
• Poor cell activity
– ATR biomarker IC50 >2.5µM
J. Med. Chem. (2011) 54, 2320
16
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
HTS hit modeled in the ATP binding
g site
Homology model for ATR based on PI3K crystal structures
Glu2380
Val2378
Tyr2365
Lys2327
Asp2494
p
Trp2379
J. Med. Chem. (2011) 54, 2320
17
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Opportunity to make beneficial interactions from the
5 h
5-phenyl
l group
Trp2379
Ser2305
Gly2385
(ATR specific)
J. Med. Chem. (2011) 54, 2320
18
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
-stack interaction with Trp2379
p
J. Med. Chem. (2011) 54, 2320
19
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Polar interaction with Ser2305 from the ortho-position
•
ATM and DNA-PK have a similarly
positioned p
p
polar residue
•
Small meta substituents don’t
improve potency or selectivity
J. Med. Chem. (2011) 54, 2320
20
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Interaction with ATR specific Gly2385 from out of plane
para substituents
para-substituents
P-Loop
Gly2385
Dihedral angle of 65° is optimal
VE-821
20
17
J. Med. Chem. (2011) 54, 2320
21
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Alternatives to the anilide are tolerated but compromise
selectivity
Tyr2755
Arg2691
Pro2775
•
Amide functions primarily to position
the aromatic group under the P-loop
J. Med. Chem. (2011) 54, 2320
22
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
VE-821 a powerful tool to probe target biology
ATR assay
HT29 cells + HU
ATM assay
M059J cells + NCS
DNA-PK assay
HT144 cells + NCS
untreated
VE-821
Stimulus +
DMSO
Stimulus +
VE-821
✔
✗
✗
IF: P-H2AX (S139)
ATR assay
HT29 cells + HU
•
DNA-PK assay
HT144 cells + NCS
>100-fold selectivity
against 50 kinases
IC50 0.8µM
23
ATM assay
M059J cells + NCS
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Nat. Chem. Biol. (2011) 7, 428
ATR inhibition increases cytotoxicity
y
y of cisplatin
p
Cisplatin
V
VE-821
• Cisplatin IC50 shifts by >10-fold
>10 fold
Synergy/Antagonism
h
10.0
0
5.0
2.5
1.3
0.6
0.3
0.2
VE-821
(M)
0.1
20.0
0
10.0
5.0
2.5
1.3
0.6
0.3
0.0
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
Cisplatin
(M)
HCT116 cancer cells, MTS assay, 96h
24
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Nat. Chem. Biol. (2011) 7, 428
Phenotype
e o ype is
s through
oug inhibition
b o o
of ATR
Nat. Chem. Biol. (2011) 7, 428
25
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
ATR inhibition enhances DNA damage
g
20µM cisplatin
20 M Cispla n
ATRi
VE-822 (M):
0
0.006 0.025 0.1
0.4
Control
-
1.6
0
0.006 0.025 0.1
0.4
Pi-Chk1-S345
ATR activity marker
Pi-H2AX-S139
DNA damage marker
Pi-KAP1-S824
DNA damage marker
1.6
Cancer cells treated for 17h with cisplatin and ATRi
Nat. Chem. Biol. (2011) 7, 428
26
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Inhibition of ATR leads to S-phase checkpoint override,
h
hyperdiploidy
di l id and
d elevated
l
t d H2AX
Hct116 cells treated with VE-821 / cisplatin for 24h. DNA content stained with PI and H2AX for
phosphorylation at Ser139
Nat. Chem. Biol. (2011) 7, 428
27
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
ATR inhibition potentiates multiple classes of DNA
damaging drug
Cisplatin
p
(Crosslinking)
Camptothecin
p
(Topoisomerase I)
Synergy/Antagonism
Synergy/Antagonism
Cisplatin
(M)
Gemcitabine
(Antimetabolite)
Taxotere
(Antimitotic)
Synergy/Antagonism
VE-821
(M)
Camptothecin
(nM)
Etoposide
(Topoisomerase II)
Synergy/Antagonism
Synergy/Antagonism
50
45
40
35
30
25
20
15
10
5
0
-5
Taxotere
(nM)
No impact with cytotoxic
drugs that don’t damage DNA
Gemcitabine
(M)
VE-821
(M)
HCT116 cancer cells, MTS assay, 96h
28
VE-821
(M)
20.0
10.0
5.0
2.5
1.3
0.6
0.3
0.0
0.000
0.000
0.001
0.002
0.003
0.006
0.013
0.025
0.050
VE-821
(M)
50
45
40
35
30
25
20
15
10
5
0
-5
20.0
10.0
5.0
2.5
1.3
0.6
0.3
0.0
0.1
0.2
0.4
0.8
1.6
3.1
6.3
12.5
VE-821
(M)
20.0
10.0
5.0
2.5
1.3
0.6
0.3
0.0
0.1
0.2
0.3
0.6
1.3
2.5
5.0
10.0
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Etoposide
(M)
Nat. Chem. Biol. (2011) 7, 428
ATR inhibition p
potentiates IR
• MiaPaCa cancer cells treated with IR ± VE-821 in normoxic conditions
(clonogenic assay)
Hypoxia
+ IR
Surviv
ving fraction
Normoxia
+ IR
Vehicle
VE-821
Vehicle
VE-821
Studies run at the Gray Institute Oxford University
Br J Cancer. (2012) 10, 291
29
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
and reverses hypoxia
yp
radiation resistance
• MiaPaCa cancer cells treated with IR ± VE-821 in normoxic or hypoxic
yp
conditions (clonogenic assay)
Hypoxia
+ IR
Surviv
ving fraction
Normoxia
+ IR
Vehicle
VE-821
Vehicle
VE-821
Studies run at the Gray Institute Oxford University
Br J Cancer. (2012) 10, 291
30
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Differential response between cancer and noncancer cells
ll
• Combination of VE
VE-821
821 and cisplatin,
cisplatin volume under the synergy surface at 96h
(95% confidence interval)
Synergy/Antagonism
VE-821
(M)
cancer
20.0
10.0
5.0
2.5
1.3
0.6
0.3
0
0.0
0.1
0.2
0.3
0.6
1.3
2.5
5.0
10.0
Synergy (Lo
og volume)
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
Cisplatin
(M)
non-cancer
Nat. Chem. Biol. (2011) 7, 428
31
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Differential response between cancer and noncancer cells
ll
• Enhanced cytotoxicity in cancer cells but only cytostasis in non-cancer cells
– Combination of VE-821 and cisplatin
Cancer cells (H23)
Non-cancer cells (HFL1)
Synergy/Antagonism
Synergy/Antagonism
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
5.0
10.0
2.5
1.3
0.6
0.3
0
0.2
0.1
0.3
VE-821 / M
0.0
1.3
1
5.0
2.5
10.0
20.0
Cisplatin / M
0.6
VE-821 / M
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
2.5
5.0
10.0
0.6
1.3
0.2
0.3
0
20.0
10.0
5.0
2.5
1.3
0.6
0
0.3
3
0.0
1
0.1
Cell death (96h)
Synergy/Antagonism
Cisplatin
/ M
Synergy/Antagonism
5.0
2.5
2
1.3
3
0.6
0.3
0.2
0.1
0.3
1.3
0.6
5.0
0
2.5
20.0
2
VE-821 / M
0.0
Cisplatin / M
10
0.0
10
0.0
5.0
0
2.5
1.3
0.6
0.3
0.2
0.1
0.3
0.0
5.0
1.3
0.6
VE-821 / M
2.5
20.0
10.0
Cell growth (24h)
10.0
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
Cisplatin / M
Nat. Chem. Biol. (2011) 7, 428
32
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Enhanced growth arrest in non-cancer cells is
reversible
ibl
H23 / HFL1 cells
ll
VE 821 + Ci
VE-821
Cisplatin
l ti (72h)
VE
VE-821
821 + Ci
Cisplatin
l ti (72h)
DMSO (72h)
7.5M VE-821, 1.25M Cisplatin
33
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Nat. Chem. Biol. (2011) 7, 428
ATR inhibition is associated with a compensatory
DDR iin non-cancer cells
ll
HFL1 normal fibroblasts
10M VE-821,
100M Cisplatin
Inhibition
of ATR
Activation
of ATM
Nat. Chem. Biol. (2011) 7, 428
34
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Synthetic lethality with ATM pathway
AT1BR
(ATM null)
20
15
15
10
10
5
5
0
0
-5
-5
20.0
10.0
5.0
2.5
1.3
0.6
0.3
0.0
VE-821
(M)
Cisplatin
(M)
VE-821
(M)
A549 (scrambled siRNA)
20.0
25
20
5.0
30
25
10.0
35
30
2.5
40
35
1.3
45
40
0.6
50
45
0.3
50
0.2
Synergy/Antagonism
20.0
5.0
Synergy/Antagonism
10.0
2.5
1.3
0.6
0.3
0.2
20.0
10.0
5.0
2.5
1.3
0.6
0.3
0.0
161BR
6
(ATM wt)
Cisplatin
(M)
A549 (siRNA p53)
Synergy/Antagonism
Synergy/Antagonism
VE-821
(M) 35
20.0
10.0
5.0
2.5
1.3
0.6
0.3
0
0.2
2
0.3
3
1.3
0.6
0
5.0
2.5
20.0
10.0
20.0
10.0
5.0
2.5
1.3
0.3
0.6
Cisplatin
(M)
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
0.0
VE-821
(M)
0.2
0
20.0
10.0
5.0
2.5
1.3
0.6
0.3
0
0.0
60
55
50
45
40
35
30
25
20
15
10
5
0
-5
Cisplatin
(M)
Nat. Chem. Biol. (2011) 7, 428
35
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
From tool molecule to lead candidate
• Optimisation to improve potency and drug-like properties
– Optimised interactions with the P
P-loop
loop
VE 821
VE-821
VE 822
VE-822
Enzyme
y
potency
p
y and selectivityy
• ATR Ki 13nM
• ATM Ki 16 000nM
• DNA-PK Ki 2200nM
Enzyme
y
potency
p
y and selectivityy
• ATR Ki <0.3nM
• ATM Ki 34nM
• DNA-PK Ki >4000nM
Cell potency
• Biomarker IC50 800nM
Cell potency
• Biomarker IC50 19nM
Solubility (pH7.4) <0.3 M
Solubility (pH7.4) 46 M
Cancer Res. (2013) 73, LB299
36
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
VE-822 modeled in ATP binding
g site
Val2378
Glu2380
Asp2330
Asp2335
Trp2379
Asp2494
Glu2479
Gl 2385
Gly2385
37
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
VE-822 markedly improves tumor responses to
cisplatin
i l ti iin PDX NSCLC model
d l
VE 822 + Cisplatin
VE-822
PDX NSCLC adenocarcinoma
VE-822 dosed at 60mg/kg PO QDx4
p
dosed at 1mg/kg
g g IP Q7D
Cisplatin
1600
Tumor volume (mm3)
T
Vehicle
Vehicle
Ci ll ti (1mg/kg)
Cisplatin
Ci
Cisplatin
(1 /k )
1200
VE-822 (60mg/kg)
VE-822
Combination
Combination
800
% off weight cha
ange
20
15
10
5
0
16 24 32 40 48 56 64
-5
Days Post Implantation
-10
400
Combinations well
tolerated
0
16
24
32
40
48
56
64
Days Post Implantation
Statistical synergy observed in 5/9 PDX NSCLC tumors
Cancer Res. (2013) 73, LB299
38
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Efficacy correlates with biomarker responses
• Mice treated with single dose of VE-822 + cisplatin and tumors
assessed for:
• Inhibition of ATR by P-Chk1 at an early time point
• Accumulation of DNA-damage
g by
y P-H2AX at late time p
point
P-Chk1
(4h post treatment)
P-H2AX
(48h post treatment)
5
Fold change in pi-H2AX
F
2.0
1.5
1.0
0.5
3
2
1
t io
n
in
at
na
pl
C
om
bi
is
C
VE
-8
22
bi
om
C
C
is
na
pl
at
tio
n
in
0
VE
-8
22
Ve
hi
cl
e
0.0
4
Ve
hi
cl
e
Fold chnage
e in pi-Chk1
2.5
Cancer Res. (2013) 73, LB299
39
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
18FLT-PET
a potential early marker for response
• Mice treated with single dose of VE-822 and cisplatin
18
FLT SUV in Tumor, Early Response
10
1.0
0.5
0.0
Baseline
40
Tumor Volume
2.0
Relative to Basseline
R
N oor m alized to B aseline
1.5
FLT SUV in Tumor
24 hours
42 hours
Vehicle
3
Relative to Bas
R
seline
18
1.5
1.0
0.5
Cisplatin
VE-822
2
Combination
1
0
0.0
Baseline
Day 6
Day 10
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Day 13
Baseline
Day 6
Day 10
Day 13
Cancer Res. (2013)
73, LB299
VE-822 markedly improves responses to IR
MiaPaCa-2
C
cell line
IR dosed at 6Gy once on day 1
VE-822 dosed orally at 60mg/kg on days -1 through 3 or 5
Vehicle
Tumo
our volume
e (mm3)
VE 822 60mg/kg PO
VE-822
IR 6Gy
X X Combination
Studies run at the Gray
Institute Oxford University
C ll D
Cell
Death
th Di
Dis. (2012 D
Dec))
Days from start of treatment
Combination well tolerated with no significant body weight loss
41
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
VE-822 does not enhance non-cancer cell tox
• Mice treated with single IR dose (6Gy) ± 3 doses of VE-822 (PO 60mg/kg Q2D)
– IR beam directed through the gut
– Animals assessed on day 5
– Combination showed beneficial efficacyy
No added effect on villi length
Apoptottic cells in
villus-c
crypt unit
%Loss o
of villus tip
(% c
control)
No enhanced apoptosis
Ve
h
VE-822
XRT
Combo
Ve
h
VE-822
XRT
Combo
Studies run at the Gray Institute Oxford University
Cell Death Dis. (2012 Dec)
42
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Summaryy
• ATR is a key mediator for the cellular response to replication stress
– Induced by many cancer drugs and IR
• Many
M
cancers appear to
t be
b addicted
ddi t d tto ATR for
f survival
i l
– Defects in alternative repair pathways
– Expression of replication stress inducing oncogenes
– Hypoxia
• Med-chem
M d h
program led
l d tto id
identification
tifi ti off VE-822,
VE 822 the
th lead
l d candidate
did t
– Potentiates the anti-tumor activity of many DNA damaging drugs and IR in
mouse models of cancer at well tolerated doses
• Normal cells tolerate inhibition of ATR with just a transient growth arrest
– Loss of function of the compensatory ATM-p53 pathway is an important
contributor
t ib t tto cellll sensitivity
iti it
43
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Acknowledgements
• Project leader
– John Pollard
• Project management
– Nathan Coates
– Janet Fernihough
• Research management
– Julian Golec
– Peter Charlton
• Biochemistry
– Joanna Long
– Paul Wang
• Cell Biology
–
–
-
44
Philip
p Reaper
p
Matthew Griffiths
Adele Peek
Amy Hall
B d Eustace
Brenda
E t
Sean Milton
Cheryl Murphy
• Biomarkers
–
–
–
–
–
–
Yong
g Gu
Matt Harding
Gereon Lauer
Chris DeFranco
M i P
Marina
Penney
Darin Takemoto
• Pharmacology
–
–
–
–
–
–
–
–
–
–
Chris
Ch
i Barnes
B
Scott Gladwell
Brinley Furey
Hakim Djeha
Stuart Hughes
Yuxin Wang
Howard Li
Dave Newsome
Diane Boucher
Mark Wood
• Imaging
–Crystal Tolman
–Mac Johnson
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
• Chemistry
–
–
–
–
–
–
–
–
Jean-Damien Charrier
Juan-Miguel Jimenez
Steve Durrant
David Kay
R
Ronald
ld K
Knegtel
t l
Somhairle MacCormick
Michael Mortimore
Michael O Donnell
–
–
–
–
–
Joanne Pinder
Alistair Rutherford
Pierre Storck
A i Vi
Anisa
Viranii
Stephen Young
• DMPK
–
–
–
–
Linda Lawes
Peter Littlewood
Jeff Moore
Tanya Hay
• Gray Inst Oxford University
– Gillies McKenna
– Ester Hammond
– Thomas Brunner
Differences in biological profile between ATR and Chk
inhibition
VE
E-822
• Panel of lung lines treated with combinations of
DDRi and varied DNA-damaging drugs for 96h
((viability
y assessed by
y MTS))
• Data shows as maximum shifts in IC50 value for the
DNA damaging drug on addition of DDRi
Percent of lines with >3-fold shifts
Percent of lines with >10-fold
shifts
AZD-7762
VE-822
Cancer Res. (2013) 73, LB299
45
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Potential as a monotherapy
py in certain p
populations
p
• Tumors with high replicative stress
•
E.g. oncogenic stress, hypoxia, DNA-repair defects
• Tumors
T
with
ith d
defects
f t in
i compensatory
t
DDR pathways
th
ATRi toxic to some cancer
but not non-cancer cells
Myc drives cell
sensitivity to ATRi
Anoxic cells highly
sensitive to ATRi
Vehicle
ATRi
Nat. Chem. Biol. (2011) 7, 428
46
J. Clin. Inv. (2012) 122, 241
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013
Control
ATRi
Br. J. Cancer (2012) 107, 291
Further improvements by optimising the sulfone
J. Med. Chem. (2011) 54, 2320
47
© 2013 Vertex Pharmaceuticals Incorporated | VXR-EU-ONC-00003 | 09/2013