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According to Synta's website, STA-9090 is a novel, synthetic, small-molecule inhibitor of heat shock protein 90 (Hsp90), being developed for treating multiple solid tumor and hematologic cancers. STA-9090 was discovered and developed internally at Synta and has a chemical structure unrelated to the first-generation, ansamycin family of Hsp90 inhibitors such as 17-AAG. In preclinical studies, STA-9090 has shown potency up to 100 times greater than the first-generation Hsp90 inhibitors as well as activity against a wider range of kinases. In in vitro and in vivo models, STA-9090 has shown potent activity against a wide range of cancer types, including lung, prostate, colon, breast, gastric, pancreatic, melanoma and certain hematologic cancers - as well as potent activity against cancers resistant to Gleevec, Sutent, Tarceva, Sprycel, and 17-AAG.

Highlight of recent study using Ganespib (STA-9090)

Ganetespib (STA-9090) in Cancer Cells with Activated  JAK/STAT Signaling (published in 2011) ganetespib exhibits potent in vitro and in vivo activity in a range of solid and hematological tumor cells that are dependent on JAK2 activity for growth and survival. Of note, ganetespib treatment results in sustained depletion of JAK2, including the constitutively active JAK2V617F mutant, with subsequent loss of STAT activity and reduced STAT-target gene expression.  (source: PLoS One. 2011 Apr 14;6(4):e18552.)

Kaplan-Meier analysis of overall survival in a leukemia model established by i.v. injection of HEL92.1.7 cells into SCID mice, which resulted in the development of disseminated disease. Beginning one day after tumor cell implantation, ganetespib was i.v. dosed at its HNSTD (25 mg/kg) on a five-times per week schedule for 3 weeks through day 19 (n = 10/group). *P,0.0001; 2-sided log-rank test. (source: PLoS One. 2011 Apr 14;6(4):e18552.)

SCID mice were subcutaneously implanted with MV4-11 acute myeloid leukemia cells. Mice bearing established MV4-11 xenografts (100–200 mm3, n = 8 mice/group) were i.v. dosed (arrowheads) with ganetespib at either 25 or 150 mg/kg once weekly for 3 weeks, or at the HNSTD of 25 mg/kg five-times per week, as indicated. % T/C values are indicated to the right of each growth curve and the error bars are the s.e.m. (source: PLoS One. 2011 Apr 14;6(4):e18552.)

Phase II trial result: Ganetespib showed clinical activity on patients with Non-small Cell Lung Cancer (published  in 2011):  According to Synta Pharmaceuticals Corp's new release (Jul 7, 2011), Ganetespib has shown encouraging single agent clinical activity and a good safety profile in pretreated advanced NSCLC patients,” said Julie Brahmer, M.D., Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital. “The case study presented today shows a patient whose ALK positive cancer had progressed on treatment with crizotinib, the most clinically advanced ALK inhibitor, who then experienced significant tumor shrinkage within the first several weeks of treatment with ganetespib. The results for ganetespib in NSCLC, particularly in patients with ALK or KRAS mutations, suggest this compound has promising potential to benefit lung cancer patients.”   Of the 23 patients in the Phase 2 trial tested for ALK translocation or rearrangement (ALK+), eight patients were ALK+ in at least one assay. Six of these eight patients (75%) showed tumor shrinkage in target lesions, one patient showed no change in tumor size, and one patient achieved stable disease (tumor growth <20%). The disease control rate in this population was 7/8 (88%), and the objective response rate (CR+PR) was 4/8 (50%).

Phase I trial result: Ganetespib Shows Clinical Activity in HER2+ and Triple Negative Metastatic Breast Cancer (published  in  2011). According to Synat's new release (December 08, 2011), "The single agent ganetespib results presented today further validates Hsp90 as a target for treating HER2-positive breast cancer and suggest Hsp90 inhibition may be an important new approach to treating triple negative breast cancer,” said Shanu Modi, M.D., Memorial Sloan-Kettering Cancer Center, the principal investigator on this study. “15% (2/13) of the patients with the HER2 gene amplification experienced a partial response in this trial and an additional 46% (6/13) achieved stable disease. These encouraging results for Hsp90 inhibition in HER2 positive disease are consistent with results from an earlier Phase 2 study of 17-AAG, a first generation Hsp90 inhibitor, in which 22% (6/27) achieved partial response and an additional 37% (10/27) achieved stable disease1. While in the prior study 17-AAG was given in combination with trastuzumab, in the current study ganetespib was given as a monotherapy. Together, these studies present compelling evidence that Hsp90 inhibition is effective in HER2-positive breast cancer.”

1. Cancer therapy using a combination of a heat-shock protein 90 inhibitory compound and a vascular endothelial growth factor receptor inhibitor By Blackman, Ronald K.; Foley, Kevin P.; Proia, David From PCT Int. Appl. (2011), WO 2011133521 A2 20111027.

2. Cancer therapy using a combination of heat-shock protein 90 inhibitory compounds and an epidermal growth factor receptor inhibitor By Blackman, Ronald K.; Kevin, Foley P.; Proia, David From PCT Int. Appl. (2011), WO 2011133520 A1 20111027.

3. Detection of circulating mRNA, microRNA, protein and vesicle markers in disease diagnosis and selection of therapies By Kuslich, Christine; Poste, George; Klass, Michael; Spetzler, David; Pawlowski, Traci From PCT Int. Appl. (2011), WO 2011127219 A1 20111013.

4. Theranostic and diagnostic methods using SPARC and HSP90 By Penny, Robert J. From PCT Int. Appl. (2011), WO 2011116181 A1 20110922.

5. Heat-shock protein-90 (HSP90) inhibitors for treatment of various clinical conditions associated with biological activity of HSP90 By Shapiro, Leland From U.S. Pat. Appl. Publ. (2011), US 20110201587 A1 20110818.

6. Detection of oncogenic mutations as markers of susceptibility of tumors to treatment with inhibitors of HSP90 and associated signaling proteins By Fritz, Christian; Normant, Emmanuel Y.; Paez, Juan Guillermo; West, Kip A. From PCT Int. Appl. (2011), WO 2011060328 A1 20110519.

7. Combination therapy using with taxanes and triazolone HSP90 inhibitory compounds for treatment of cancer By Blackman, Ronald K.; Foley, Kevin Paul; Proia, David From PCT Int. Appl. (2011), WO 2011049946 A1 20110428.

8. STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer By Wang, Yisong; Trepel, Jane B.; Neckers, Leonard M.; Giaccone, Giuseppe From Current Opinion in Investigational Drugs (BioMed Central) (2010), 11(12), 1466-1476.

9. Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias By Bansal, Hima; Bansal, Sanjay; Rao, Manjeet; Foley, Kevin P.; Sang, Jim; Proia, David A.; Blackman, Ronald K.; Ying, Weiwen; Barsoum, James; Baer, Maria R.; et al From Blood (2010), 116(22), 4591-4599.

10. Methods for providing personalized medicine tests ex vivo for hematological neoplasms By Ballesteros, Juan; Bennett, Teresa; Primo, Daniel; Orfao, Alberto; Jackson, Coyt; Lago, Santiago; Matoses, Maria; Suarez, Lilia; Sapia, Sandra; Bosanquet, Andrew; et al From PCT Int. Appl. (2010), WO 2010135468 A1 20101125.

11. Met amplification and HSP90 inhibitors. Comment on Wang S, et al. cell cycle 2009; 8:2050-6 By Giaccone, Giuseppe; Rajan, Arun From Cell Cycle (2009), 8(17), 2682.

12. Preparation of triazole derivatives as Hsp90 inhibitors By Chimmanamada, Dinesh U.; Zhang, Shije; Lee, Chi-Wan; Przewloka, Teresa; Ying, Weiwen From PCT Int. Appl. (2009), WO 2009075890 A2 20090618.

13. Preparation of substituted imidazoles, pyrazoles, and triazoles, particularly hydroxyaryl-substituted triazolethiols, as treatments for cancers associated with mutations in c-Met By Du, Zhenjian; Foley, Kevin From PCT Int. Appl. (2008), WO 2008153730 A2 20081218.

14. The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors By Lin, Tzu-Yin; Bear, Misty; Du, Zhenjian; Foley, Kevin P.; Ying, Weiwen; Barsoum, James; London, Cheryl From Experimental Hematology (New York, NY, United States) (2008), 36(10), 1266-1277.

15. Preparation of triazoles as inhibitors of topoisomerase II and Hsp90 By Du, Zhenjian; Song, Minghu; Ying, Weiwen From PCT Int. Appl. (2008), WO 2008112199 A1 20080918.

16. Preparation of substituted triazoles for treating inflammatory disorders By Zhou, Dan; Qin, Shuzen; Ying, Weiwen From PCT Int. Appl. (2008), WO 2008057246 A2 20080515.

17. Preparation of triazoles and related compounds as Hsp90 inhibitors By Ying, Weiwen From PCT Int. Appl. (2008), WO 2008051416 A2 20080502.

18. Compound of resorcinol derivative with polymer having good water solubility, stability and high antitumor activity By Nakamura, Masaharu; Kitagawa, Masayuki; Yamamoto, Keiichirou; Seno, Chieko From PCT Int. Appl. (2008), WO 2008041610 A1 20080410.

19. Triazole derivatives as HSP90 modulators and their preparation, pharmaceutical compositions and use in the treatment of angiogenesis By Ying, Weiwen; Foley, Kevin From PCT Int. Appl. (2008), WO 2008021364 A2 20080221.

20. Substituted triazole compounds that modulate Hsp90 activity and methods for identifying same By Ying, Weiwen From PCT Int. Appl. (2007), WO 2007139960 A2 20071206.

21. Methods for preparing aryltriazoles with ability to modulate HSP90 activity By Lee, Chi-Wan; James, David; Zhang, Shijie; Ying, Weiwen; Chimmanamada, Dinesh U.; Chae, Junghyun; Przewloka, Teresa From PCT Int. Appl. (2007), WO 2007139952 A2 20071206.

22. Triazole derivatives and their method for treating proliferative disorders associated with protooncogene products and their preparation By Du, Zhenjian; Foley, Kevin From PCT Int. Appl. (2007), WO 2007139951 A2 20071206.

23. Triazole derivatives and their preparation and method for treating non-Hodgkin's lymphoma By Foley, Kevin From PCT Int. Appl. (2007), WO 2007140002 A2 20071206.

24. Preparation of triazoles as Hsp90 inhibitors for treating cancer By Ying, Weiwen; James, David; Zhang, Shijie; Przewloka, Teresa; Chae, Junghyun; Chimmanamada, Dinesh U.; Lee, Chi-Wan; Kostik, Elena; Ng, Howard P.; Foley, Kevin; et al From PCT Int. Appl. (2006), WO 2006055760 A1 20060526.