WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 200424
Description: AZD4877 is a synthetic kinesin spindle protein (KSP) inhibitor with potential antineoplastic activity. KSP inhibitor AZD4877 selectively inhibits microtubule motor protein KSP (also called kinesin-5 or Eg5), which may result in the inhibition of mitotic spindle assembly; activation of the spindle assembly checkpoint; induction of cell cycle arrest during the mitotic phase; and cell death in tumor cells that are actively dividing. Because KSP is not involved in postmitotic processes, such as neuronal transport, this agent may be less likely to cause the peripheral neuropathy often associated with the tubulin-targeting agents. Eg5 is essential for the formation of bipolar spindles and the proper segregation of sister chromatids during mitosis.
MedKoo Cat#: 200424
Chemical Formula: C28H33N5O2S
Exact Mass: 503.2355
Molecular Weight: 503.66
Elemental Analysis: C, 66.77; H, 6.60; N, 13.90; O, 6.35; S, 6.37
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Synonym: AZD4877 AZD-4877; AZD 4877.
IUPAC/Chemical Name: N-(3-aminopropyl)-N-(1-(5-benzyl-3-methyl-4-oxo-4,5-dihydroisothiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl)-4-methylbenzamide
InChi Key: SMFXSYMLJDHGIE-UHFFFAOYSA-N
InChi Code: InChI=1S/C28H33N5O2S/c1-18(2)24(32(16-8-15-29)27(34)22-13-11-19(3)12-14-22)25-30-26-23(20(4)31-36-26)28(35)33(25)17-21-9-6-5-7-10-21/h5-7,9-14,18,24H,8,15-17,29H2,1-4H3
SMILES Code: O=C(N(CCCN)C(C1=NC(SN=C2C)=C2C(N1CC3=CC=CC=C3)=O)C(C)C)C4=CC=C(C)C=C4
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
The following data is based on the product molecular weight 503.66 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|
1: Gerecitano JF, Stephenson JJ, Lewis NL, Osmukhina A, Li J, Wu K, You Z, Huszar D, Skolnik JM, Schwartz GK. A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies. Invest New Drugs. 2012 May 22. [Epub ahead of print] PubMed PMID: 22615058.
2: Marquis L, Tran M, Choi W, Lee IL, Huszar D, Siefker-Radtke A, Dinney C, McConkey DJ. p63 expression correlates with sensitivity to the Eg5 inhibitor ZD4877 in bladder cancer cells. Cancer Biol Ther. 2012 May 1;13(7):477-86. Epub 2012 May 1. PubMed PMID: 22361733.
3: Theoclitou ME, Aquila B, Block MH, Brassil PJ, Castriotta L, Code E, Collins MP, Davies AM, Deegan T, Ezhuthachan J, Filla S, Freed E, Hu H, Huszar D, Jayaraman M, Lawson D, Lewis PM, Nadella MV, Oza V, Padmanilayam M, Pontz T, Ronco L, Russell D, Whitston D, Zheng X. Discovery of (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin -6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a kinesin spindle protein inhibitor and potential anticancer agent. J Med Chem. 2011 Oct 13;54(19):6734-50. Epub 2011 Sep 7. PubMed PMID: 21899292.
4: Esaki T, Seto T, Ariyama H, Arita S, Fujimoto C, Tsukasa K, Kometani T, Nosaki K, Hirai F, Yagawa K. Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors. Arch Drug Inf. 2011 Jun;4(2):23-31. PubMed PMID: 21765863; PubMed Central PMCID: PMC3130141.
5: Infante JR, Kurzrock R, Spratlin J, Burris HA, Eckhardt SG, Li J, Wu K, Skolnik JM, Hylander-Gans L, Osmukhina A, Huszar D, Herbst RS. A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2012 Jan;69(1):165-72. Epub 2011 Jun 3. PubMed PMID: 21638123.
6: Kantarjian HM, Padmanabhan S, Stock W, Tallman MS, Curt GA, Li J, Osmukhina A, Wu K, Huszar D, Borthukar G, Faderl S, Garcia-Manero G, Kadia T, Sankhala K, Odenike O, Altman JK, Minden M. Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia. Invest New Drugs. 2012 Jun;30(3):1107-15. Epub 2011 Apr 15. PubMed PMID: 21494838.
According to AstraZenca, AZD4877 was discontinued from development due to insufficient clinical activity.(source: http://www.astrazenecaclinicaltrials.com/other-drug-products/discontinued-products/).
Phase I/II trials: Eg5 (kinesin spindle protein) is a microtubule motor protein, essential for centrosome separation during mitosis. This Phase I/II, open-label, multicenter, two-part study investigated AZD4877 , a potent Eg5 inhibitor, in patients with acute myeloid leukemia. Primary objectives were to determine the maximum tolerated dose (MTD) (part A), assess efficacy (part B) and determine the pharmacokinetic profile (parts A and B). Secondary objectives included assessment of safety and tolerability. AZD4877 was administered at a range of doses (2, 4, 7, 10, 13, 16 and 18 mg/day) as a 1-hour intravenous infusion on three consecutive days of a continuous 2-week schedule. The MTD in part A was defined as 16 mg/day based on dose-limiting stomatitis at 16 and 18 mg/day, hyperbilirubinemia at 16 mg/day and palmar-plantar erythrodysesthesia syndrome at 18 mg/day. Systemic exposure to AZD4877 generally increased with increasing dose whereas half-life was not dose dependent. No evaluable patients experienced a complete remission (CR) or CR with incomplete blood count recovery (CRi), demonstrating no evidence of AZD4877 efficacy in this population. Evidence of monoasters in all but the 4 mg/day dose group provided proof of mechanism for AZD4877 . This study was terminated due to lack of efficacy. (ClinicalTrials.gov identifier NCT00486265). (source: http://www.ncbi.nlm.nih.gov/pubmed/21494838).
Phase I/II trials: