SNS-314_ A POTENT INHIBITOR OF AURORA KINASES_ HAS PRECLINICAL

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SNS-314_ A POTENT INHIBITOR OF AURORA KINASES_ HAS PRECLINICAL Powered By Docstoc
					                                    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

				
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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."