Danusertib
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    WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 200846

CAS#: 827318-97-8

Description: Danusertib, also known as PHA-739358, is a small-molecule 3-aminopyrazole derivative with potential antineoplastic activity. Aurora kinase inhibitor PHA-739358 binds to and inhibits the Aurora kinases, which may result in cell growth arrest and apoptosis in tumor cells in which Aurora kinases are overexpressed. This agent may preferentially bind to and inhibit Aurora B kinase. Aurora kinases, a family of serine-threonine kinases, are important regulators of cellular proliferation and division.


Price and Availability

Size
Price

5mg
USD 265
Size
Price

Size
Price

Danusertib, purity > 98%, is in stock. Current shipping out time is about 2 weeks after order is received. CoA, QC data and MSDS documents are available in one week after order is received.


Chemical Structure

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Theoretical Analysis

MedKoo Cat#: 200846
Name: Danusertib
CAS#: 827318-97-8
Chemical Formula: C26H30N6O3
Exact Mass: 474.23794
Molecular Weight: 474.55
Elemental Analysis: C, 65.80; H, 6.37; N, 17.71; O, 10.11


Synonym: PHA739358; PHA-739358; PHA 739358; Danusertib.

IUPAC/Chemical Name: (R)-N-(5-(2-methoxy-2-phenylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

InChi Key: XKFTZKGMDDZMJI-HSZRJFAPSA-N

InChi Code: InChI=1S/C26H30N6O3/c1-30-12-14-31(15-13-30)20-10-8-19(9-11-20)25(33)27-24-21-16-32(17-22(21)28-29-24)26(34)23(35-2)18-6-4-3-5-7-18/h3-11,23H,12-17H2,1-2H3,(H2,27,28,29,33)/t23-/m1/s1

SMILES Code: O=C(NC1=NNC2=C1CN(C([C@H](OC)C3=CC=CC=C3)=O)C2)C4=CC=C(N5CCN(C)CC5)C=C4


Technical Data

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:
>5 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).

Harmonized System Code:
293490


Additional Information

PHA-739358 exhibits inhibitory activity against all known Aurora kinases as well as other cancer-relevant kinases such as the Bcr-Abl tyrosine kinase, including its multidrug-resistant T315I mutant. This mutation is responsible for up to 25% of all clinically observed resistances in CML patients undergoing Imatinib therapy. However, this particular mutation is predicted to play an even more important clinical role in the future, since in addition to Imatinib, it also confers resistance to second-generation Bcr-Abl inhibitors such as Nilotinib, Dasatinib, and Bosutinib. Therefore, combined Aurora and Bcr-Abl inhibition (the latter including high-grade resistance conferring mutations) with compounds such as Danusertib represents a promising new strategy for treatment of Bcr-Abl positive leukemias, especially those in second and third line of treatment. see http://www.ncbi.nlm.nih.gov/pubmed/20072840.  
 
 


References

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3: Yuan CX, Zhou ZW, Yang YX, He ZX, Zhang X, Wang D, Yang T, Pan SY, Chen XW, Zhou SF. Danusertib, a potent pan-Aurora kinase and ABL kinase inhibitor, induces cell cycle arrest and programmed cell death and inhibits epithelial to mesenchymal transition involving the PI3K/Akt/mTOR-mediated signaling pathway in human gastric cancer AGS and NCI-N78 cells. Drug Des Devel Ther. 2015 Mar 2;9:1293-318. doi: 10.2147/DDDT.S74964. eCollection 2015. PubMed PMID: 25767376; PubMed Central PMCID: PMC4354435.

4: Li JP, Yang YX, Liu QL, Zhou ZW, Pan ST, He ZX, Zhang X, Yang T, Pan SY, Duan W, He SM, Chen XW, Qiu JX, Zhou SF. The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells. Drug Des Devel Ther. 2015 Feb 17;9:1027-62. doi: 10.2147/DDDT.S74412. eCollection 2015. PubMed PMID: 25733818; PubMed Central PMCID: PMC4338784.

5: Hole S, Pedersen AM, Lykkesfeldt AE, Yde CW. Aurora kinase A and B as new treatment targets in aromatase inhibitor-resistant breast cancer cells. Breast Cancer Res Treat. 2015 Feb;149(3):715-26. doi: 10.1007/s10549-015-3284-8. Epub 2015 Feb 10. PubMed PMID: 25667100.

6: Schöffski P, Besse B, Gauler T, de Jonge MJ, Scambia G, Santoro A, Davite C, Jannuzzo MG, Petroccione A, Delord JP. Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study. Ann Oncol. 2015 Mar;26(3):598-607. doi: 10.1093/annonc/mdu566. Epub 2014 Dec 8. PubMed PMID: 25488684.

7: Illert AL, Seitz AK, Rummelt C, Kreutmair S, Engh RA, Goodstal S, Peschel C, Duyster J, von Bubnoff N. Inhibition of Aurora kinase B is important for biologic activity of the dual inhibitors of BCR-ABL and Aurora kinases R763/AS703569 and PHA-739358 in BCR-ABL transformed cells. PLoS One. 2014 Nov 26;9(11):e112318. doi: 10.1371/journal.pone.0112318. eCollection 2014. PubMed PMID: 25426931; PubMed Central PMCID: PMC4245092.

8: Diculescu VC, Enache TA. Electrochemical evaluation of Abelson tyrosine-protein kinase 1 activity and inhibition by imatinib mesylate and danusertib. Anal Chim Acta. 2014 Oct 3;845:23-9. doi: 10.1016/j.aca.2014.06.025. Epub 2014 Jun 17. PubMed PMID: 25201268.

9: Cheung CH, Sarvagalla S, Lee JY, Huang YC, Coumar MS. Aurora kinase inhibitor patents and agents in clinical testing: an update (2011 - 2013). Expert Opin Ther Pat. 2014 Sep;24(9):1021-38. doi: 10.1517/13543776.2014.931374. Epub 2014 Jun 26. Review. PubMed PMID: 24965505.

10: Zhang Q, Descamps O, Hart MJ, Poksay KS, Spilman P, Kane DJ, Gorostiza O, John V, Bredesen DE. Paradoxical effect of TrkA inhibition in Alzheimer's disease models. J Alzheimers Dis. 2014;40(3):605-17. doi: 10.3233/JAD-130017. PubMed PMID: 24531152; PubMed Central PMCID: PMC4091737.

11: Catucci G, Occhipinti A, Maffei M, Gilardi G, Sadeghi SJ. Effect of human flavin-containing monooxygenase 3 polymorphism on the metabolism of aurora kinase inhibitors. Int J Mol Sci. 2013 Jan 28;14(2):2707-16. doi: 10.3390/ijms14022707. PubMed PMID: 23358255; PubMed Central PMCID: PMC3588010.

12: Xie L, Meyskens FL Jr. The pan-Aurora kinase inhibitor, PHA-739358, induces apoptosis and inhibits migration in melanoma cell lines. Melanoma Res. 2013 Apr;23(2):102-13. doi: 10.1097/CMR.0b013e32835df5e4. PubMed PMID: 23344158; PubMed Central PMCID: PMC4077197.

13: Winter GE, Rix U, Carlson SM, Gleixner KV, Grebien F, Gridling M, Müller AC, Breitwieser FP, Bilban M, Colinge J, Valent P, Bennett KL, White FM, Superti-Furga G. Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. Nat Chem Biol. 2012 Nov;8(11):905-12. doi: 10.1038/nchembio.1085. Epub 2012 Sep 30. PubMed PMID: 23023260; PubMed Central PMCID: PMC4038039.

14: Meulenbeld HJ, Bleuse JP, Vinci EM, Raymond E, Vitali G, Santoro A, Dogliotti L, Berardi R, Cappuzzo F, Tagawa ST, Sternberg CN, Jannuzzo MG, Mariani M, Petroccione A, de Wit R. Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU Int. 2013 Jan;111(1):44-52. doi: 10.1111/j.1464-410X.2012.11404.x. Epub 2012 Aug 29. PubMed PMID: 22928785.

15: Ochiana SO, Pandarinath V, Wang Z, Kapoor R, Ondrechen MJ, Ruben L, Pollastri MP. The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposing. Eur J Med Chem. 2013 Apr;62:777-84. doi: 10.1016/j.ejmech.2012.07.038. Epub 2012 Jul 31. PubMed PMID: 22889561; PubMed Central PMCID: PMC3516633.

16: Fraedrich K, Schrader J, Ittrich H, Keller G, Gontarewicz A, Matzat V, Kromminga A, Pace A, Moll J, Bläker M, Lohse AW, Hörsch D, Brümmendorf TH, Benten D. Targeting aurora kinases with danusertib (PHA-739358) inhibits growth of liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model. Clin Cancer Res. 2012 Sep 1;18(17):4621-32. doi: 10.1158/1078-0432.CCR-11-2968. Epub 2012 Jul 2. PubMed PMID: 22753592.

17: Fei F, Lim M, Schmidhuber S, Moll J, Groffen J, Heisterkamp N. Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib). Mol Cancer. 2012 Jun 21;11:42. doi: 10.1186/1476-4598-11-42. PubMed PMID: 22721004; PubMed Central PMCID: PMC3489684.

18: Zhang Y, Zhang B, Feng WH, Li YY, Cao XC. [Molecular mechanism of Aurora kinase inhibitor PHA739358 in inhibited proliferation and induced apoptosis of breast cancer cells]. Zhonghua Yi Xue Za Zhi. 2012 Jan 3;92(1):45-9. Chinese. PubMed PMID: 22490658.

19: Meulenbeld HJ, Mathijssen RH, Verweij J, de Wit R, de Jonge MJ. Danusertib, an aurora kinase inhibitor. Expert Opin Investig Drugs. 2012 Mar;21(3):383-93. doi: 10.1517/13543784.2012.652303. Epub 2012 Jan 13. Review. PubMed PMID: 22242557.

20: Catucci G, Gilardi G, Jeuken L, Sadeghi SJ. In vitro drug metabolism by C-terminally truncated human flavin-containing monooxygenase 3. Biochem Pharmacol. 2012 Feb 15;83(4):551-8. doi: 10.1016/j.bcp.2011.11.029. Epub 2011 Dec 8. PubMed PMID: 22177984.