G.Wells | 7 June 2011
PARP-1 Inhibitors in Oncology
The Discovery and Development of CEP-9722,an Orally Active Prodrug for the Treatment of Cancer
G.Wells | 7 June 2011
Rationale for PARP-1 Inhibitors in Oncology
• PARP comprises a family of at least 14 related enzymes some of which play a pivotal role in DNA repair.
• The primary member, Poly (ADP-ribose) polymerase 1 (PARP-1), is a nuclear enzyme that catalyzes the synthesis of poly-ADP ribose chains from NAD+ as part of the DNA repair process.
• Signals and recruits other proteins to repair damaged DNA and can be activated by single strand breaks in DNA.
• Inhibitors of PARP-1 have shown promise in oncology through potentiation of the anti-tumor activity of radiation or chemotherapeutic DNA damaging agents.
G.Wells | 7 June 2011
PARP-1 - Background
• Inverse correlation of PARP-1 activity with the degree of cell differentiation. Tumors have increased PARP activity as compared to the corresponding normal tissue.
• PARP inhibitors as chemopotentiators: Benzamides, Isoquinolones, Nicotinamide derivatives in vitro and in vivo.
• Potentiates the activity of TMZ, bleomycin, cisplatin, and radiation in human and murine tumor models
G.Wells | 7 June 2011
Role of PARP-1 in DNA Repair
N
C
N
C
A. de Murcia & M. de Murcia (1994) TIBS 19, 172
DNA Damage
ADP-ribose
PARP Activation
NAD+ ATP
G.Wells | 7 June 2011
Role of PARP-1 in DNA Repair
N
C
N
C
A. de Murcia & M. de Murcia (1994) TIBS 19, 172
DNA Damage
ADP-ribose
PARP Activation
NAD+ ATP
DNA damage repaired
G.Wells | 7 June 2011
Role of PARP-1 in DNA Repair
N
C
N
C
A. de Murcia & M. de Murcia (1994) TIBS 19, 172
DNA Damage
ADP-ribose
PARP Activation
NAD+ ATP
DNA damage repaired
Healthy cell
G.Wells | 7 June 2011
Role of PARP-1 in DNA Repair
N
C
N
C
A. de Murcia & M. de Murcia (1994) TIBS 19, 172
PARP Inhibitor
DNA damage persists
DNA Damage
ADP-ribose
PARP Activation
NAD+
ATP
Damage repaired,Healthy cell
G.Wells | 7 June 2011
Role of PARP-1 in DNA Repair
N
C
N
C
A. de Murcia & M. de Murcia (1994) TIBS 19, 172
PARP Inhibitor
DNA damage persists
DNA Damage
ADP-ribose
PARP Activation
NAD+
ATP
Damage repaired,Healthy cell
Apoptosis,Cell death
G.Wells | 7 June 2011
PARP activity, NAD+, and ATP levels are interdependent
Ha, H. C.; Neurobiology of Disease 7, 225–239 (2000)
G.Wells | 7 June 2011
Clinical Path Forward
• Glioblastoma w/TMZ - # 1 Choice
o Poor single agent response rate (~5%) allows for clear improvement using combination therapy with p.o. TMZ
o Reasonable size and duration of clinical trials with TMZ
o Unmet therapeutic need for GBM; other therapeutic indications for TMZ- sarcoma, melanoma, colon carcinoma and CNS lymphoma
o Substantial supportive pre-clinical data with TMZ
• Therapeutic Endpoints: Improved Response Rate and “Time to Event” outcome
G.Wells | 7 June 2011
N
NH2
O
Ribose
Ribose Adenine
PP
+
NAD+
Known PARP inhibitors mimic nicotinamide binding at the NAD+ site and are planar aromatic ring systems containing a bidentate H-bonding group
PARP-1 inhibitors based on NAD+ substrate
N OO
H
NH2
NH2
O
NH2
4-ANI3-AB
Ki = 4M Ki ~ 150nM
G.Wells | 7 June 2011
N
X
NO
H
H
R
O
NN O
H
R
N O
N
O
H
Me2N
Pfizer/Agouron - Indoles/Benzimidazoles
Iconix - PhenanthridinonesGuilford - Phthalazinones
Earlier Competitor PARP-1 Scaffolds
G.Wells | 7 June 2011
NH
CH3
O
NH2
NH2
O
PD128763
Ki = 70nM
3-AB
o inc. radiation sensitivity of Chinese hamster V79 cellso Radiat Res; 126(3), 367 (1991)
NH
N
NH2
O
OH
NH
NH
O
F
NH
NU-1085 AG14699
+ crystal structure+ modelling
Ki = 6nM Ki < 5nM
o potentiates TMZ and TP growth inhib. in human tumor cell lineso Clin Cancer Res; 6, 2860 (2000)
Proof of Concept
o Clinical trials candidate
G.Wells | 7 June 2011
NH2
O
NH
N
NH
ABT-888 (Veliparib)
o Potentiates TMZ, Cisplatin, radiation in syngeneic and xenograft tumor models o Clin Cancer Res; 13, 2728 (2007)
o Completing Phase 2 trials w/TMZ
o Irreversible inhibitoro Excellent Phase 2 resultso First PARP inhibitor in Phase 3 trialso Failed primary endpoint
NH2
O
I
O2N
BSI-201 (Iniparib)
(Sanofi-Aventis)
N
N
O
F
O
NHN
O
AZD-2281 (Olaparib)
o Cancelled Phase 3 trials for breast cancero Commencing Phase 3 for ovarian cancer
NN
NH
ONH2
HCl
MK-4827
o Phase 1 trial for various cancerso Well toleratedo Commencing Phase 2 for Mantle Cell Lymphoma
In the Clinic
G.Wells | 7 June 2011
Early CEP Library Screening Hit - Pyrrolocarbazole Imide
N
NO O
H
H12
34
5 7
A
B CD
E
CEP-3498 I C50= 35 nM
• Screening of Cephalon’s internal library identified a pyrrolocarbazole as a potent inhibitor of PARP-1.
• Improvements Needed: Potency Cellular Permeability/Activity Solubility
G.Wells | 7 June 2011
N OO
H
NH2
4-ANI
PARP-1 Modeling
Apply structure-based design to optimize potency and cell activity
Obtained 2PAX from PDB (Protein Data Bank) - Catalytic Fragment Of Poly(ADP-Ribose) Polymerase complexed with 4-amino-1,8-naphthalimide Chicken PARP (PARP-CF), 87% homologous with the human form
G.Wells | 7 June 2011
G.Wells | 7 June 2011
Ala898
Glu988
Gly863
Tyr907
3-position
Modeling of CEP-3499 with PARP-CF
NH
NH
O
CEP-3499
Wells, Bihovsky; BMCL, 16, 1151 (2006)
G.Wells | 7 June 2011
PARP Inhibitor Discovery Flow
In Vitro Cytotoxicity Assays (PARP inhibitors + Chemotherx.)
In Vivo Chemo-Potentiation Studies
GBMs /TMZ, HT-29/Irinotecan
Significant shift in tumor versus normal cell kill versus chemotherx. alone
In Vivo PAR Accumulation Assay
No enhanced humanmyelotoxicity in vitro
Biochemical efficacy in vivo
Cmpd Scale-Up
Significant potentiation of anti-tumor efficacy versus chemotherx. alone; acceptable systemic tolerability.
Go/No GoDecision
PK and Tolerability in Rodents
rh PARP Inhibition Assay
PC12 cells/H2O2 insultAssay for Inhibition of NAD+ Depletion
In vitro and in vivo evaluation on normal tissues; clinical chemistry and histopathology
IC50 < 50 nM
50% recovery @ < 1 uM>90% max. recovery
Criteria
G.Wells | 7 June 2011
General Route to Pyrrolocarbazoles
XO
R1
R2
NH
NH
OO
R1
R2
NH
NH
X
NH
OO
O
R
R R
NC CO2EtNH
O O
X
R2
R1
R
(X = NH, S, O)
(Key Intermediates)
> Heteroaryl analogs - Indole - Benzofuran - Benzothiophene
> Carbazole Imide analogs> Right-hand modifications
> Carbazole Lactam analogs
(X = NH, S, O)
+
G.Wells | 7 June 2011
PARP-1 Activity of Pyrrolocarbazole Lactam Isomers
CEP Structure PARP IC50 (nM)
Imide (CEP-3498)
35
7-oxo(CEP-3499)
90
5-oxo(CEP-3500)
~10, 000
NH
NH
O5
NH
NH
O 7
NH
NH
OO
• PARP activity resides in the 7-oxo isomer, the 5-oxo is inactive for PARP
• Imide CEP-3498 is 3-fold more potent than the 7-oxo lactam CEP-3499 (enhanced H-bonding?)
G.Wells | 7 June 2011
Pyrrolocarbazole Right-Hand Modifications
NH R1
R2
NH
O O
CEP R1, R2 PARP IC50 (nM)
3498 35
5558 ~10,000
2520 > 10,000
5848 ~ 10,000O
• The cyclopentyl ring is critical for potency
G.Wells | 7 June 2011
PARP-1 Inhibition of Pyrrolocarbazoles
NH R1
R2
NH
O O
CEP R1 R2 PARP IC50 (nM)
3498 -CH2CH2CH2- 35
1526 H H ~ 10, 000
5653 Methyl Methyl 700
5674 Methyl H 5000
5729 H Methyl ~2000
5706 Ethyl Propyl > 10,000
• Ring-opened analogs showed decreased potency
Tao, Wells; BMCL; 16, 938 (2006)
G.Wells | 7 June 2011
PARP-1 Inhibition of Benzofuran/Benzothiophene Analogs
X
NH
O O
CEP X PARP IC50 (nM)
3498 NH 35
6297 S > 10, 000
6373 O > 10, 000
• Indole N-H an essential binding function for potency• Corresponding N-Me also inactive
G.Wells | 7 June 2011
PARP-1 Inhibition of Truncated Analogs
CEP Structure PARP IC50 (nM)
6012 40
6011 2220
5775 750
NH
NH
O O
NH
O O
NH
O O
NH
• Des-Aryl CEP-6012 was equipotent with carbazole CEP-3498• SAR supports the model and the importance of the N-H interaction
G.Wells | 7 June 2011
Indole-Cyclopentyl Series
R IC50 (nM)
H 40
Br 5
CN 6
CH2NH2 89
N
N
OO
H
H
R
Tao, Wells; BMCL; 16, 938 (2006)
• Smaller MW - potentially improved physical properties• Single digit nM leads
G.Wells | 7 June 2011
SAR of Methoxy Analogs
NAD+ Rec. PC12 cells
R CEP IC50 (nM) Conc. For 50%
Rec. (uM)
H 3498 35 >30
2-OMe 8062 224 3.0
3-OMe 8091 32 1.0
4-OMe 8983 20 0.3
3,4-OMe 9712 21 <1.0
N
N
OO
H
H
R
12
34
• Data confirms model for 3- and 4-substituents for optimal activity
• CEP-8983 is a potent, high permeability compound (PAMPA = 7.3 x 10-6 cm/sec)
G.Wells | 7 June 2011
3-Aminoalkyl-1-Carba-Series
R CEP IC50 (nM) NAD+ rec. @1 M
CH2NH2 6800 22 73%
CH2NMe2 7264 20 69%
CH2NEt2 7273 17 97%
CH2NHEt 7271 32 102%
CH2NnPr2 7272 16 104%
CH2NnBu2 7317 28 50%
CH2NBn2 7318 293 40%
CH2NC4H8 7826 35 83%
CH2CH2NH2 7828 36 49%
N
N
OO
H
H
R
12
34
• Generally good solubility, potency and cell activity• CEP-6800-HCl demonstrated >10 mg/mL aq. solubility• CEP-6800 showed toxicity, low brain levels, poor PK
G.Wells | 7 June 2011
3-Alkoxy-1-Carba-Series
R CEP IC50 (nM) NAD+ rec. 1 M
OH 7958 27 58%
OAc 7957 33 59%
OMe 8091 32 41%
OCH2CH2OEt 8323 59 27%
OCH2CH2NEt2 8371 88 21%
OCH2CH2CH2NEt2 8349 100 25%
OCH2CH2NC4H8O 8969 22 17%
N
N
OO
H
H
R
12
34
• Evaluated amino and ether alkyl spaced groups
• Morpholino-CEP-8969 showed good enzyme activity and solubility, but low cellular activity
G.Wells | 7 June 2011
CEP R PARP
IC50 (nM) NAD+ Rec. in
PC12 cells (1 M)
H2O sol. (mg/mL)
9010
10
53%
>10
9013
30
52%
>10
9016
22
44%
---
9027
15
58%
>10
3-Carbamate and Amide Derivatives
/
O
N
N
O
O
N
HN
/
NN O
O
/OH
N
N
OO
H
H
R
NN
NN O
O
N
H
/
H
Wells, Bihovsky; BMCL, 16, 1151 (2006)
• Identified potent, cell permeable inhibitors with good water solubility• Low brain levels observed with carbamates
G.Wells | 7 June 2011
General Synthesis of Alkoxy Analogs
NH O
NH
OH
NH
NH
O O
NH
NH
OO
NH
(iPr)3SiO (iPr)3SiO(iPr)3SiO
R-OR-O
1) nBuLi, CO2
THF, -78oC
2) tBuLi
3)
Et2O
AcOH
RX, CsF
AcCN, 50 oC AcOH, r.t.
p-Chloranil
AcOH, 95 oC
G.Wells | 7 June 2011
Summary SAR
N
N
O
H
H
O
4-Alkoxy important - potency - cell activity
3-Substitution - potency - solubility
Substitution not tolerated
N-H essential(O or S inactive)
Cyclopentylrequired
7-oxo required
G.Wells | 7 June 2011
PARP-1 model for 1-Aza analog of CEP-8983
• Favorable H-bond postulated between 1-aza group and amide of Met890
G.Wells | 7 June 2011
Synthetic Approach to Aza-analog CEP-8315
N NH
O
N NH
OH
NH
O O
N NH
NH
OO
N NH
1) nBuLi, CO2
THF, -78oC
2) tBuLi
3)
Et2O
AcOH
p-Chloranil
AcOH, 95 oC
CEP-8315 (IC50= 3 nM)
• Further confirms model, binding pose• Most potent analog prepared
G.Wells | 7 June 2011
Proposed 1-Aza-4-Alkoxy Series
N
NO O
H
H
O
N N
NO O
H
H
N N
NO O
H
OR
H
CEP-8983
(IC50 = 20 nM)
CEP-8315
(IC50 = 3 nM)
• Good cellular activity • Better potency
• Best of both worlds?
G.Wells | 7 June 2011
1-Aza-4-Alkoxy Synthetic Challenges
N NH
N NH
Cl
N NH
OR
N NH
OH
1) MCPBA, DME
2) aq. K2CO3 (pH 9)
3) POCl3, reflux
4) aq.K2CO3 (pH 9)
(50%)
5% NaOH/ROH
160-180oC, 18-24h
(20-50%)
NaOHo Expen$iveo Limited supply
• Chloride displacement tricky, requires sealed (“bomb”) reactor
• Ethers thermally sensitive, give variable yields and purity profile
G.Wells | 7 June 2011
1-Aza-4-Alkoxy Series Synthetic Challenges
X N
R
HX N
R
H
R X % Yield
H C 70-80OMe C 60-70 H N 40-50OMe N 0-10____________________
1. n-BuLi/THF, then CO2
2. t-BuLi, then c-pentanone
3. HCl
• Series requires alternate approach
G.Wells | 7 June 2011
1-Aza-4-Alkoxy Series Synthetic Challenges
N NSO2Ph
OR
N NSO2Ph
I
OMe
N NSO2Ph
OMeO
OH
N NSO2Ph
OMeO
DN N
SO2Ph
OMeO
B(OCH3)2
N NSO2Ph
SnMe3
OMe
t-BuLi, THF, -78oC;
then c-pentanone
(0-10%)
t-BuLi, THF-78oC - 0oC; then D2O
(50-60%)
t-BuLi, THF-78oC - 0oC;then (MeO)3B
LDA, THF-78oC - 0oC;then Me3SnCl
LDA, THF, TMEDA, -20oC;then I2
(40-60%)
G.Wells | 7 June 2011
Diene Problem “Solved”
N N
OR
SO2Ph
IN N
H
ORSnBu3
N N
NO O
H
H
OR
(5-steps from 7-azaindole)
cat. PdCl2(PPh3)2
DMF, 90oC;then NaOH, EtOH
(~50%)(2 steps)
(~50%)
• Suitable method for small (mg-gm) quantities
G.Wells | 7 June 2011
SAR of 1-Aza analogs
CEP X R IC50 (nM) % NAD+ rec.
(1 M)
3498 CH H 35 46% (30 M)
8315 N H 3 50%
9222 N 3-Me 2 46%
9667 N 3-OMe 4 44%
9397 N 4-OMe 4 94%
N
NX
OO
H
H
R
1
2
34
• 1-Aza group confers order-of-magnitude greater potency• 3- and 4-substituents tolerated – opportunity for solubility, improved PK
G.Wells | 7 June 2011
SAR of 1-Aza-4-Subst’d- analogs
CEP R IC50 (nM) % NAD rec. 1
M
9397 OMe 4 94%
9890 OEt 5 62%
9955 OCH2CH2OMe 10 74%
9956 OCH2CH2OEt 11 63%
9891 Cl 9 87%
9371 NMe2 121 42%
N
NN
OO
H
H
R
1
2
34
• Non-basic 4-substituents well-tolerated
• Aza-series ultimately discontinued due to synthetic challenges, non-scalability, expense, and poor solubility
G.Wells | 7 June 2011
OH
NH
O
NH
Si
O
O
NH
Si
OH
O
NH
Si
NH
OMe
(i-Pr)3SiCl
ImidazoleDMF
then CO2
CH3I ,CsF
CH3CN
(95%)
n-BuLi, THF, -65oC t-BuLi, THF, -65oC
then
(92%)
(91%)
(92%)
HOAc, Et2O
Synthetic Process for Drug Candidate CEP-8983
G.Wells | 7 June 2011
NH
OMe
NH
NH
O
OOMeN
HOO
NH
NH
O
OOMe
HOAc
p-Chloranil
HOAc
CEP-8983
(80%) (94%)
o MW = 306o Poor solubility (<<1mg/mL)o Difficult purification (DMF/Al2O3)
Synthetic Process for CEP-8983 (cont.)
G.Wells | 7 June 2011
NH
NH
O
OOMe
N N
NH
NO
OOMe
NH N
CEP-8983 CEP-9722
CH2O, EtOH
(96%)
o MW = 306o Poor solubility (<<1mg/mL)o Difficult purification (DMF/Al2O3)
o MW = 418o Crystallized from THF/hexaneso Stable solido Aqueous soluble salts
Synthetic of Prodrug CEP-9722
• Other related prodrug analogs (amide, sulfonamide, carbamate, urea, N,O-aminal) were more or less stable and/or soluble
G.Wells | 7 June 2011
N
N
N
N
OO
H
R
R CEP Solubility (pH 4.2)
Ascorbic Acid (mg/mL)
T90 Stability (hrs)
OMe 9722 ~20 18
OCH2CH2OMe 16345 >40 >20
OCH2CH2OEt 16346 8 22
Solubility and Aqueous Stability of N-Methylpiperazinyl Aminal Prodrug Analogs
• CEP-16345 and CEP-9722 met solubility and stability criteria at a pH sufficient for I.V. delivery in the clinic
G.Wells | 7 June 2011
Stable, Soluble Mannich Base Gluconates
N
N
O
X
H
H
OO
N
N
N
N
O
X
H
OON N H
HO2C
OH
OH
OH
OH
OH
, CH2O, EtOH
+ 2
CEP-8983 (X = C)CEP-9397 (X = N)
CEP-9722 (X = C)CEP-10306 (X = N)
(then gluconic acid)
• Gluconic acid salt gave optimal aqueous solubility and stability
• Decomposes in-vivo to CEP-8983/9397, formaldehyde, and methylpiperazine
G.Wells | 7 June 2011
Single Crystal Structure of CEP-9722
• Confirms bonding of prodrug moiety at imide, not indole
G.Wells | 7 June 2011
N
N
OO
H
H
R4
hERG Structure-Activity Relationships: 4-Alkoxy SAR
• Diether substitution at the 4-position reduced hERG channel activity in patch clamp assay
R4 CEP PARP IC50
(nM)
hERG IC50 (M)
OMe 8983 20 2.1
OCH2CH2OMe 9274 11 82
OCH2CH2OEt 9430 10 22
G.Wells | 7 June 2011
Dose Escalation Study with CEP-9722/8983 in Rats
• i.v. administration of CEP-9722 (3, 10, 30 mg/kg dose equivalents) to rats showed dose related increases in plasma level exposure of CEP-8983
G.Wells | 7 June 2011
The Effects of CEP-8983 and CEP-9397 on Temozolomide Mediated Toxicity in U251MG Cells
0 50 100 150 200 250 3000
50
100
TMZ alone
TMZ+0.1 M CEP-8983TMZ+0.3 M CEP-8983TMZ+1.0 M CEP-8983TMZ+3.0 M CEP-8983TMZ +10 M CEP-8983
*
*
***
*******
**
****
**p0.01; ***p0.1- TMZ alone as compared to TMZ + 1.0 M CEP-8983;*p0.05; **p0.01; ***p0.001- TMZ alone as compared to TMZ + 3.0 MCEP-8983; *p0.05; **p0.01; ****p0.0001- TMZ alone as compared toTMZ + 10.0 M CEP-8983 by Mann Whitney Rank Sum test or t-test whereappropriate.
TMZ (M)
Rel
ativ
e C
ell
Nu
mb
er (
%)
0 50 100 150 200 250 3000
50
100
TMZ alone
TMZ+0.1 M CEP-9397TMZ+0.3 M CEP-9397TMZ+1.0 M CEP-9397TMZ+3.0 M CEP-9397
TMZ +10 M CEP-9397
***************
*************
**
**
*
**
*p0.05; **p0.01 - TMZ alone as compared to TMZ + 0.1 M CEP-9397; *p0.05; **p0.01***p0.001 - TMZ alone as compared to TMZ + 0.3 M CEP-9397; *p0.05; ***p0.001****p0.0001 - TMZ alone as compared to TMZ + 1.0 M CEP-9397; *p0.05; ***p0.001;****p0.0001- TMZ alone as compared to TMZ + 3.0 M CEP-9397; *p0.05; ***p0.001;****p0.0001- TMZ alone as compared to TMZ + 10.0 M CEP-9397 by Mann Whitney RankSum test or t-test where appropriate.
TMZ (M)
Rel
ativ
e C
ell
Nu
mb
er (
%)
• CEP-8983 and CEP-9397 potentiated the growth inhibitory effects of TMZ in U251MG cells
G.Wells | 7 June 2011
0 100 200 3000
50
100
TMZ alone
TMZ+0.1 M CEP-8983TMZ+0.3 M CEP-8983TMZ+1.0 M CEP-8983TMZ+3.0 M CEP-8983TMZ +10 M CEP-8983
********
**
*
***
**
******
********* *
**
****
**
********
TMZ (M)
Rel
ativ
e C
ell
Nu
mb
er (
%)
0 100 200 3000
50
100
TMZ alone
TMZ+0.1 M CEP-9397TMZ+0.3 M CEP-9397TMZ+1.0 M CEP-9397TMZ+3.0 M CEP-9397TMZ +10 M CEP-9397
**
**
***
****
**
*
**
***
***
**
**
***
******
********
*******
TMZ (M)
Rel
ativ
e C
ell
Nu
mb
er (
%)
*p≤0.5, ** p≤0.01-TMZ alone as compared to TMZ + 0.3 µM CEP-8983; * p≤0.5 ** p≤0.01, **** p≤0.0001- p≤0.01-TMZ alone as compared to TMZ + 1.0 µM CEP-8983; *** p≤0.001 **** p≤0.0001- p≤0.01-TMZ alone as compared to TMZ + 3.0 µM CEP-8983; **p≤0.01****p≤0.0001-TMZ alone as compared to TMZ + 10.0 µM CEP-8983 by Mann-Whitney Rank Sum Test or t-test where appropriate.
*p≤0.5, ** p≤0.01-TMZ alone as compared to TMZ + 0.1 µM CEP-9397 *p≤0.5, ** p≤0.01-TMZ alone as compared to TMZ + 0.3 µM CEP-9397; * p≤0.5 ** p≤0.01, *** p≤0.001- p≤0.01-TMZ alone as compared to TMZ + 1.0 µM CEP-9397; ** p≤0.01 *** p≤0.001 **** p≤0.0001- p≤0.01-TMZ alone as compared to TMZ + 3.0 µM CEP-9397; **p≤0.01, ***p≤0.001, ****p≤0.0001-TMZ alone as compared to TMZ + 10.0 µM CEP-9397 by Mann-Whitney Rank Sum Test or t-test where appropriate.
The Effects of CEP-8983 and CEP-9397 on Temozolomide Mediated Toxicity in NB1691 Cells
• CEP-8983 and CEP-9397 potentiated the growth inhibitory effects of TMZ in TMZ-resistant tumor cell lines
G.Wells | 7 June 2011
Phase 1 commenced June 2009
Open-label study to evaluate the safety, pharmacokinetics, and pharmacodynamics as single-agent oral therapy and as combination therapy with temozolomide in patients with advanced or metastatic solid tumors.
Expected completion May-June 2011
Phase 2 IND filed Jan 2011
Evaluate safety and tolerability of maximum tolerated dose (MTD) found in Phase 1, and investigate CEP-9722 oral efficacy as a single agent.
Additional combination studies with Gemcitabin/Cisplatin planned
Expected completion July 2013
CEP-9722 Advanced to Clinical Trials
G.Wells | 7 June 2011
Oncology
Candace Burns Jennifer Grobelny Kathryn Hunter Sonya Pritchard Hugh Zhao Susan Jones-Bolin Bruce Ruggeri
Acknowledgements
Chung Ho Park Dandu Reddy Sankar Chatterjee Ron Bihovsky Gregory Wells
Chemistry
Mary Birchler Laura Gwinn Jean Husten Bruce Jones
Biochemistry
Seetha Murthy Damaris Rolon-Steele Kelli Zeigler Lisa Aimone Mark Ator
Jim Diebold Ming Tao Derek Dunn Allison Zulli Bob Hudkins
Fox Chase Cancer Center
Andres Klein-Szanto
G.Wells | 7 June 2011
Extra slides
G.Wells | 7 June 2011
N
NN
NN
O
ONH2
NN
NHN
ONH2
NH
H2O
(-CO2)
TMZ MTIC
TMZ – Hydrolysis gives active form
Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.
G.Wells | 7 June 2011
29th AnnualJ.P. Morgan Healthcare ConferenceJanuary 10-12, 2011
Cephalon Oncology Pipeline
G.Wells | 7 June 2011
G.Wells | 7 June 2011
Wang; Am J Cancer Res; 1(3):301-327 (2011)
G.Wells | 7 June 2011
Wang; Am J Cancer Res; 1(3):301-327 (2011)