3-[(Aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-Thiophenecarboxamide Chemical Properties

Boiling point:

547.6±50.0 °C(Predicted)

Density 

1.38

storage temp. 

-20°

solubility 

Soluble in DMSO (up to at least 25 mg/ml).

pka

9.06±0.20(Predicted)

form 

solid

color 

Yellow or brown

Stability:

Stable for 1 year as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.

3-[(Aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-Thiophenecarboxamide Usage And Synthesis

Description

Actively proliferating cells experience blocks at certain checkpoints in the cell cycle when DNA damage is detected. These checkpoints allow for DNA damage repair before further cell cycle progression. Targeting signaling pathways to selectively inhibit repair at these checkpoints in tumor cells is of considerable interest to cancer therapeutics. AZD 7762 selectively inhibits the activity of checkpoint kinases (Chk) 1 and Chk2 (IC₅₀s = 5 nM) by competitively and reversibly binding their respective ATP-binding sites (K_i = 3.6 nM for Chk1). AZD 7762 abrogates DNA damage-induced S and G₂ checkpoints with an EC₅₀ value of 10 nM and potentiates the efficacy of DNA-damage repair prohibitive agents, gemcitabine and topotecan, both in vitro and in various tumor xenografts by modulating downstream checkpoint pathway proteins.

Uses

AZD 7762 is studied as an cancer therapeutic agent due to its selective inhibitory activities towards checkpoint kinases, chk1 and chk2 by reversibly binding their respective ATP-binding sites within tumor cells. Recent research has also indicated AZD 7762 to possess enhancing effects towards other chk1 inhibitor lethality in glioblastoma cells.

Definition

ChEBI: 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide is an aromatic amide and a member of thiophenes.

in vivo

IC 50

Chk1: 5 nM (IC₅₀); Chk2: 5 nM (IC₅₀)

References

[1] SONYA D ZABLUDOFF. AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies.[J]. Molecular Cancer Therapeutics, 2008, 7 9: 2955-2966. DOI:10.1158/1535-7163.mct-08-0492
[2] JAMES B MITCHELL. In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762.[J]. Clinical Cancer Research, 2010, 16 7: 2076-2084. DOI:10.1158/1078-0432.ccr-09-3277
[3] MEREDITH A MORGAN. Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair.[J]. Cancer research, 2010, 70 12: 4972-4981. DOI:10.1158/0008-5472.can-09-3573
[4] HU LEI. Chk1 inhibitors overcome imatinib resistance in chronic myeloid leukemia cells[J]. Leukemia research, 2018, 64: Pages 17-23. DOI:10.1016/j.leukres.2017.11.007
[5] SYED AHMAD  John E S  Gary L Johnson. Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity[J]. Biochemical and biophysical research communications, 2015, 463 4: Pages 888-893. DOI:10.1016/j.bbrc.2015.06.029
[6] YOUNG HWAN PARK . Repositioning of anti-cancer drug candidate, AZD7762, to an anti-allergic drug suppressing IgE-mediated mast cells and allergic responses via the inhibition of Lyn and Fyn[J]. Biochemical pharmacology, 2018, 154: Pages 270-277. DOI:10.1016/j.bcp.2018.05.012

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