Get documents about "SNS-314_ A POTENT INHIBITOR OF AURORA KINASES_ HAS PRECLINICAL
W
Description
SNS, full name of the Social Networking Services, the social networking services, specifically refers to is designed to help people build social networks of Internet applications. Also refers to the popularity of social maturity of the existing information carriers, such as SMS text messaging service. Another common explanation SNS: Full name Social Network Site, or "social networking" or "social net."
Document Sample
SNS-314, A POTENT INHIBITOR OF AURORA KINASES, HAS PRECLINICAL ANTI-TUMOR ACTIVITY AND INDUCES APOPTOSIS
Marc J. Evanchik, Jennifer N. Hogan, Jennifer P. Arbitrario, Jeffrey L. Kumer, Ute Hoch, Anthony R. Howlett, Kristin Zimmerman, W. Michael Flanagan, Jeffrey A. Silverman and Pietro Taverna
Sunesis Pharmaceuticals, Inc., South San Francisco, CA
Abstract # 5648 SNS-314 Displays Potent Anti-Tumor Activity in Multiple Xenograft Models SNS-314 Decreases Histone H3 Phosphorylation in Skin and Bone Marrow
The Aurora family of serine/threonine kinases (Aurora A, Aurora B, and Aurora C) Phospho-histone H3 in epidermis from SNS-314 treated Phospho-histone H3 in bone marrow in mice is
mice is reduced compared to vehicle treated mice reduced after SNS-314 administration
plays a key role in cells orderly progression through mitosis. Elevated expression HCT-116 (CRC): TGI = 95.6% PC-3 (Prostate): TGI = 67.5%
levels of Aurora kinases have been detected in a high percentage of melanoma, SNS-314 @ 150 m/k IP biwx3 SNS-314 @ 170 mg/kg biw x3
colon, breast, ovarian, gastric, and pancreatic tumors, and in a subset of these 1500 Irinotecan @ 100 mg/kg qw x3 1250
Paclitaxel @ 30 mg/kg qod x5
Vehicle qdx5
tumors the AURKA locus (20q13) is amplified. SNS-314, a novel aminothiazole- Vehicle biw x 3
Tum Volum (m 3)
Tumor Volume (mm3)
dosing
e m
1250
derived urea, is a selective inhibitor of Aurora kinases A, B, and C with IC50 values dosing 1000
Vehicle
Vehicle
in the low nanomolar range. SNS-314 potently inhibits cell proliferation and 1000
750
induces polyploidy (> 4N DNA) in a diverse panel of human cancer cell lines. In the 750
present study we investigated the pharmacodynamic effects and in vivo activity of 500
500
or
SNS-314 in human tumor xenograft models. SNS-314 displayed potent anti-tumor 250
activity in HCT-116 (colon), PC-3 (prostate), CALU-6 (NSCLC) and MDA-MB-231 250
(breast) models. Tumor growth inhibition in these xenograft models ranged from 0
SNS-314
0
SNS-314
0 10 20 30 40 0 10 20 30 40 50
67.5 to 96.6% on a bi-weekly administration for 3 weeks. Following SNS-314 drug
Days Days
administration, endoreduplication and sustained pro-apoptotic effects measured by
increased PARP cleavage and Caspase activation in tumor samples were observed. Calu-6 (Lung): TGI = 91.4% MV 4-11 (AML): TGI = 75.6%
We also evaluated SNS-314 dependent effects in surrogate tissues as potential SNS-314 @ 170 m/k biw x3 Vehicle biw x 3
biomarkers and indicators of response; inhibition of Histone H3 phosphorylation 1000 Irinotecan @ 100 qw x3 2000 SNS-314 150 mg/kg biw x 3
was observed in bone marrow and skin epidermis obtained from mice after Day 4 Day 18 Day 11 Day 18
Tum Volum m 3
Vehicle biw x3
Tum Volum (m 3)
e m
dosing
e m
exposure to SNS-314 at drug levels that are efficacious and well tolerated in 750 1500
xenograft models. SNS-314 displays favorable pharmacokinetics with measurable
dosing Apoptosis is Induced in Xenograft Tumors After a Single Dose of SNS-314
drug levels sustained for more than 96 hours post-dose in the HCT-116 tumor. 500 1000
These drug levels were associated with prolonged inhibition of Histone H3 PARP cleavage becomes evident 3 hours after PARP cleavage is dose and time dependent
or
or
phosphorylation, an established substrate of Aurora Kinase B. Combined, these 250 500 dose and is maintained for at least 12 hours
data suggest that SNS-314 may be an effective therapeutic agent for the treatment Vehicle 50 mpk 100 mpk
0
of diverse human malignancies. SNS-314 is currently under investigation in a Phase 0 5 10 15 20 25
0 Vehicle 3 hr 6 hr 12 hr
1 study for the treatment of patients with solid tumors.
0 10 20 30 40
cleaved PARP
Days Days 2 hr
cleaved PARP Histone H3
β-actin
SNS-314 Plasma Concentrations Correlate with Inhibition of Histone H3 HCT-116 tumor bearing mice were treated with cleaved PARP
SNS-314 is a Selective Inhibitor of Aurora Kinases Phosphorylation in HCT-116 Tumors a single 170 mg/kg IP dose of SNS-314
Histone H3
6 hr
Low doses of SNS-314 modulate Histone H3 5 µM SNS-314 in plasma produces maximal cleaved PARP 24 hr
O O O phosphorylation 8 inhibition Histone H3
100 10
N S MV-411 tumor bearing mice were treated
administration, U/mL
administration, U/mL
H 3C OH with a single IP dose of SNS-314
pHH3 1 hour post
pHH3 1 hour post
N N Cl 7
[SNS-314], uM
HN S H H 10
Conclusions
S 1 5 6
N Molecular Weight: 527.04 (MSA salt); 430.93 (free base) Nonclinical pharmacology data strongly support clinical investigation of SNS-314 for treatment of
tumors in Phase 1 trials
0.1 5
N SNS-314 is a potent multi-Aurora kinase inhibitor with attractive pharmacologic properties
Highly specific Aurora inhibitor
• SNS-314 has an average IC50 of 9 nM for Aurora A, 31 nM for Aurora B, and 3 nM for 0.01 0 4
Aurora C 0 5 10 15 20 25 0 5 10 15 20 Broadly active and well tolerated in vivo in several xenograft tumor models using an
• SNS 314 binds the active form of Aurora A in an extended conformation SNS-314 Dose, mg/kg Plasma [SNS-314] uM intermittent dosing schedule
• SNS-314 was tested against a panel of 219 kinases to determine its selectivity profile Prolonged in vivo apoptotic effects
Vehicle 1 mpk 2 mpk 5 mpk 170 mg/kg SNS-314 produces maximal inhibition for
–Seven kinases out of the 219 show an IC50 lower than 100 nM p-Histone H3 up to 24 hours Favorable pharmacokinetic properties
–Fourteen kinases had an IC50 value between 100 and 1000 nM Histone H3 Antitumor activity consistent with Aurora Kinase inhibition and supported by
6 hr 9 hr 24 hr
• SNS-314 is a potent inhibitor of cell proliferation (IC50 range 1.8-24.4 nM) and induces pharmacodynamic markers in skin and tumors
Vehicle 10 mpk 20 mpk Vehicle SNS-314 Vehicle SNS-314 Vehicle SNS-314
polyploidy (>4N DNA) (IC50 range 4.2-93 nM) in a diverse panel of human cancer cell The safety and tolerability of SNS-314 is currently being evaluated in a phase 1 dose-escalation
lines p-Histone H3 p-Histone H3
Histone H3 clinical trial in patients with advanced solid tumors ClinicalTrials.gov Identifier: NCT00519662
Histone H3
PDF available at: http://www.sunesis.com/science/presentations.php
