WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 206217
CAS#: 908115-27-5 (free base)
Description: PF-04929113, also known as SNX-5422; is a synthetic prodrug targeting the human heat-shock protein 90 (Hsp90) with potential antineoplastic activity. Although the mechanism of action remains to be fully elucidated, Hsp90 inhibitor SNX-5542 is rapidly converted to SNX-2112, which accumulates in tumors relative to normal tissues. SNX-2112 inhibits Hsp90, which may result in the proteasomal degradation of oncogenic client proteins, including HER2/ERBB2, and the inhibition of tumor cell proliferation.
MedKoo Cat#: 206217
Name: PF-04929113 free base
CAS#: 908115-27-5 (free base)
Chemical Formula: C25H30F3N5O4
Exact Mass: 521.22499
Molecular Weight: 521.53
Elemental Analysis: C, 57.57; H, 5.80; F, 10.93; N, 13.43; O, 12.27
Synonym: SNX5422; SNX-5422; SNX 5422; PF4929113; PF-4929113; PF 4929113; PF04929113; PF 04929113; PF-04929113.
IUPAC/Chemical Name: (1r,4r)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl glycinate
InChi Key: AVDSOVJPJZVBTC-CTYIDZIISA-N
InChi Code: InChI=1S/C25H30F3N5O4/c1-24(2)10-18-21(19(34)11-24)22(25(26,27)28)32-33(18)14-5-8-16(23(30)36)17(9-14)31-13-3-6-15(7-4-13)37-20(35)12-29/h5,8-9,13,15,31H,3-4,6-7,10-12,29H2,1-2H3,(H2,30,36)/t13-,15-
SMILES Code: NCC(O[C@H]1CC[C@H](NC2=CC(N3N=C(C(F)(F)F)C4=C3CC(C)(C)CC4=O)=CC=C2C(N)=O)CC1)=O
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||PF-04929113 (SNX-5422) is a potent and selective HSP90 inhibitor with Kd of 41 nM and induces Her-2 degradation with IC50 of 37 nM.|
|In vitro activity:||All compounds summarized showed potent antiproliferative activity against a broad range of cancer cell types (Table 5). Compound (10) exhibited potent effects on Her2 stability and caused expected up-regulation of Hsp70 (Table 6). Additionally, treatment with the inhibitor down regulated both the MAPK and AKT signaling pathways as measured by the loss of p-S6 and p-ERK in treated cells. These pathways are implicated in uncontrolled cellular division and antiapoptotic signaling and have been targeted for drug development. Reference: J Med Chem. 2009 Jul 23;52(14):4288-305. https://doi.org/10.1021/jm900230j|
|In vivo activity:||Shown in Figure 8 is the in vivo antitumor activity of PF-04929113 (10) in an HT-29 human colon tumor xenograft model. The compound was orally administered to mice bearing subcutaneous tumors 3 times a week for 3 weeks (qod × 3/2 × 3) at 5, 10, 25, and 50 mg/kg. The 50 mg/kg dose was the most efficacious, demonstrating a 67% growth delay over vehicle control. Median time to end point (TTE) for the 50 mg/kg group was 43.2 days compared to 25.9 days for vehicle control. Two of 10 animals survived to the end of the study (61 days). The 25 mg/kg dose showed tumor growth delay but at a much lower percentage (14%). Median TTE was not statistically significant over vehicle control. On the basis of body weight measurements and clinical observations, compound 10 was well tolerated at all dose levels tested. No treatment related deaths were observed. Reference: J Med Chem. 2009 Jul 23;52(14):4288-305. https://doi.org/10.1021/jm900230j|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 521.53 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|In vitro protocol:||1. Huang KH, Veal JM, Fadden RP, Rice JW, Eaves J, Strachan JP, Barabasz AF, Foley BE, Barta TE, Ma W, Silinski MA, Hu M, Partridge JM, Scott A, DuBois LG, Freed T, Steed PM, Ommen AJ, Smith ED, Hughes PF, Woodward AR, Hanson GJ, McCall WS, Markworth CJ, Hinkley L, Jenks M, Geng L, Lewis M, Otto J, Pronk B, Verleysen K, Hall SE. Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J Med Chem. 2009 Jul 23;52(14):4288-305. doi: 10.1021/jm900230j. PMID: 19552433.|
|In vivo protocol:||1. Huang KH, Veal JM, Fadden RP, Rice JW, Eaves J, Strachan JP, Barabasz AF, Foley BE, Barta TE, Ma W, Silinski MA, Hu M, Partridge JM, Scott A, DuBois LG, Freed T, Steed PM, Ommen AJ, Smith ED, Hughes PF, Woodward AR, Hanson GJ, McCall WS, Markworth CJ, Hinkley L, Jenks M, Geng L, Lewis M, Otto J, Pronk B, Verleysen K, Hall SE. Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J Med Chem. 2009 Jul 23;52(14):4288-305. doi: 10.1021/jm900230j. PMID: 19552433. 2. Lamoureux F, Thomas C, Yin MJ, Kuruma H, Fazli L, Gleave ME, Zoubeidi A. A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis. Clin Cancer Res. 2011 Apr 15;17(8):2301-13. doi: 10.1158/1078-0432.CCR-10-3077. Epub 2011 Feb 24. Erratum in: Clin Cancer Res. 2011 Jul 15;17(14):4916. PMID: 21349995; PMCID: PMC4437585.|
1: Kim SH, Kang JG, Kim CS, Ihm SH, Choi MG, Yoo HJ, Lee SJ. The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of anaplastic thyroid carcinoma cells. Endocrine. 2016 Feb;51(2):274-82. doi: 10.1007/s12020-015-0706-7. Epub 2015 Jul 29. PubMed PMID: 26219406.
2: Dunna NR, Bandaru S, Akare UR, Rajadhyax S, Gutlapalli VR, Yadav M, Nayarisseri A. Multiclass comparative virtual screening to identify novel Hsp90 inhibitors: a therapeutic breast cancer drug target. Curr Top Med Chem. 2015;15(1):57-64. PubMed PMID: 25579569.
3: Infante JR, Weiss GJ, Jones S, Tibes R, Bauer TM, Bendell JC, Hinson JM Jr, Von Hoff DD, Burris HA 3rd, Orlemans EO, Ramanathan RK. Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours. Eur J Cancer. 2014 Nov;50(17):2897-904. doi: 10.1016/j.ejca.2014.07.017. Epub 2014 Sep 25. PubMed PMID: 25262379.
4: Debnath A, Shahinas D, Bryant C, Hirata K, Miyamoto Y, Hwang G, Gut J, Renslo AR, Pillai DR, Eckmann L, Reed SL, McKerrow JH. Hsp90 inhibitors as new leads to target parasitic diarrheal diseases. Antimicrob Agents Chemother. 2014 Jul;58(7):4138-44. doi: 10.1128/AAC.02576-14. Epub 2014 May 12. PubMed PMID: 24820073; PubMed Central PMCID: PMC4068574.
5: Lamoureux F, Thomas C, Yin MJ, Fazli L, Zoubeidi A, Gleave ME. Suppression of heat shock protein 27 using OGX-427 induces endoplasmic reticulum stress and potentiates heat shock protein 90 inhibitors to delay castrate-resistant prostate cancer. Eur Urol. 2014 Jul;66(1):145-55. doi: 10.1016/j.eururo.2013.12.019. Epub 2013 Dec 29. PubMed PMID: 24411988; PubMed Central PMCID: PMC4079118.
6: Zagouri F, Sergentanis TN, Chrysikos D, Papadimitriou CA, Dimopoulos MA, Psaltopoulou T. Hsp90 inhibitors in breast cancer: a systematic review. Breast. 2013 Oct;22(5):569-78. doi: 10.1016/j.breast.2013.06.003. Epub 2013 Jul 17. Review. PubMed PMID: 23870456.
7: Reddy N, Voorhees PM, Houk BE, Brega N, Hinson JM Jr, Jillela A. Phase I trial of the HSP90 inhibitor PF-04929113 (SNX5422) in adult patients with recurrent, refractory hematologic malignancies. Clin Lymphoma Myeloma Leuk. 2013 Aug;13(4):385-91. doi: 10.1016/j.clml.2013.03.010. Epub 2013 Jun 10. PubMed PMID: 23763921.
8: Jha KN, Coleman AR, Wong L, Salicioni AM, Howcroft E, Johnson GR. Heat shock protein 90 functions to stabilize and activate the testis-specific serine/threonine kinases, a family of kinases essential for male fertility. J Biol Chem. 2013 Jun 7;288(23):16308-20. doi: 10.1074/jbc.M112.400978. Epub 2013 Apr 18. PubMed PMID: 23599433; PubMed Central PMCID: PMC3675569.
9: Zagouri F, Bournakis E, Koutsoukos K, Papadimitriou CA. Heat shock protein 90 (hsp90) expression and breast cancer. Pharmaceuticals (Basel). 2012 Sep 12;5(9):1008-20. doi: 10.3390/ph5091008. PubMed PMID: 24280702; PubMed Central PMCID: PMC3816649.
10: Rajan A, Kelly RJ, Trepel JB, Kim YS, Alarcon SV, Kummar S, Gutierrez M, Crandon S, Zein WM, Jain L, Mannargudi B, Figg WD, Houk BE, Shnaidman M, Brega N, Giaccone G. A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin Cancer Res. 2011 Nov 1;17(21):6831-9. doi: 10.1158/1078-0432.CCR-11-0821. Epub 2011 Sep 9. PubMed PMID: 21908572; PubMed Central PMCID: PMC3207004.
11: Lamoureux F, Thomas C, Yin MJ, Kuruma H, Beraldi E, Fazli L, Zoubeidi A, Gleave ME. Clusterin inhibition using OGX-011 synergistically enhances Hsp90 inhibitor activity by suppressing the heat shock response in castrate-resistant prostate cancer. Cancer Res. 2011 Sep 1;71(17):5838-49. doi: 10.1158/0008-5472.CAN-11-0994. Epub 2011 Jul 7. PubMed PMID: 21737488.
12: Lamoureux F, Thomas C, Yin MJ, Kuruma H, Fazli L, Gleave ME, Zoubeidi A. A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis. Clin Cancer Res. 2011 Apr 15;17(8):2301-13. doi: 10.1158/1078-0432.CCR-10-3077. Epub 2011 Feb 24. Erratum in: Clin Cancer Res. 2011 Jul 15;17(14):4916. PubMed PMID: 21349995; PubMed Central PMCID: PMC4437585.
13: Jain L, Gardner ER, Venitz J, Giaccone G, Houk BE, Figg WD. Determination of PF-04928473 in human plasma using liquid chromatography with tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Nov 15;878(30):3187-92. doi: 10.1016/j.jchromb.2010.09.017. Epub 2010 Sep 29. PubMed PMID: 20951100; PubMed Central PMCID: PMC2980813.
14: Fadden P, Huang KH, Veal JM, Steed PM, Barabasz AF, Foley B, Hu M, Partridge JM, Rice J, Scott A, Dubois LG, Freed TA, Silinski MA, Barta TE, Hughes PF, Ommen A, Ma W, Smith ED, Spangenberg AW, Eaves J, Hanson GJ, Hinkley L, Jenks M, Lewis M, Otto J, Pronk GJ, Verleysen K, Haystead TA, Hall SE. Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90. Chem Biol. 2010 Jul 30;17(7):686-94. doi: 10.1016/j.chembiol.2010.04.015. PubMed PMID: 20659681.
15: Huang KH, Veal JM, Fadden RP, Rice JW, Eaves J, Strachan JP, Barabasz AF, Foley BE, Barta TE, Ma W, Silinski MA, Hu M, Partridge JM, Scott A, DuBois LG, Freed T, Steed PM, Ommen AJ, Smith ED, Hughes PF, Woodward AR, Hanson GJ, McCall WS, Markworth CJ, Hinkley L, Jenks M, Geng L, Lewis M, Otto J, Pronk B, Verleysen K, Hall SE. Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J Med Chem. 2009 Jul 23;52(14):4288-305. doi: 10.1021/jm900230j. PubMed PMID: 19552433.
16: Rice JW, Veal JM, Barabasz A, Foley B, Fadden P, Scott A, Huang K, Steed P, Hall S. Targeting of multiple signaling pathways by the Hsp90 inhibitor SNX-2112 in EGFR resistance models as a single agent or in combination with erlotinib. Oncol Res. 2009;18(5-6):229-42. PubMed PMID: 20225761.
17: Okawa Y, Hideshima T, Steed P, Vallet S, Hall S, Huang K, Rice J, Barabasz A, Foley B, Ikeda H, Raje N, Kiziltepe T, Yasui H, Enatsu S, Anderson KC. SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. Blood. 2009 Jan 22;113(4):846-55. doi: 10.1182/blood-2008-04-151928. Epub 2008 Oct 23. PubMed PMID: 18948577; PubMed Central PMCID: PMC2630270.
18: Taldone T, Gozman A, Maharaj R, Chiosis G. Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr Opin Pharmacol. 2008 Aug;8(4):370-4. doi: 10.1016/j.coph.2008.06.015. Epub 2008 Jul 31. Review. PubMed PMID: 18644253; PubMed Central PMCID: PMC2760289.
Hsp90 is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signaling proteins, such as HER2/ERBB2, AKT, RAF1, BCR-ABL, and mutated p53, as well as many other molecules that are important in cell cycle regulation or immune responses.