1262849-73-9 Usage
Uses
CCT241533 is an inhibitor of checkpoint kinase 2, which is a potential antitumor and radioprotectant.
Biological Activity
chk2 is a checkpoint kinase involved in the atm-mediated response to double-strand dna breaks. inhibitors of chk2 may increase the efficacy of genotoxic cancer therapies. cct241533 has been identified and characterized as a novel chk2 kinase inhibitor.in silico: x-ray crystallography confirmed that cct241533 bound to chk2 in the atp pocket. overall, the binding mode was found to be very highly conserved relative to previous compounds, with all of the key hydrogen bond interactions maintained. the potency gained with cct241533 therefore appears to be due to the presence of the two methoxy substituents occupying the solvent exposed region of the enzyme, and contributions from the isopropyl alcohol substituent, which may participate in a second intramolecular hydrogen bond to the quinazoline exocyclicnh [2].
in vitro
cct241533 inhibits chk2 with an ic50 of 3 nmol/l and shows minimal cross-reactivity against a panel of kinases at 1 mmol/l. cct241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines [1]. moreover, as the most potent chk2 inhibitor identified in the series, cct241533 shows potent selectivity (63-fold) over chk1 and low herg inhibition (hergic50=22 μm) [2].
references
[1] anderson ve, walton mi, eve pd, boxall kj, antoni l, caldwell jj, aherne w, pearl lh, oliver aw, collins i, garrett md. cct241533 is a potent and selective inhibitor of chk2 that potentiates the cytotoxicity of parp inhibitors. cancer res. 2011;71(2):463-72. [2] caldwell jj, welsh ej, matijssen c, anderson ve, antoni l, boxall k, urban f, hayes a, raynaud fi, rigoreau lj, raynham t, aherne gw, pearl lh, oliver aw, garrett md, collins i. structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2. j med chem. 2011;54(2):580-90.
Check Digit Verification of cas no
The CAS Registry Mumber 1262849-73-9 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,6,2,8,4 and 9 respectively; the second part has 2 digits, 7 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 1262849-73:
(9*1)+(8*2)+(7*6)+(6*2)+(5*8)+(4*4)+(3*9)+(2*7)+(1*3)=179
179 % 10 = 9
So 1262849-73-9 is a valid CAS Registry Number.
1262849-73-9Relevant articles and documents
Structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2
Caldwell, John J.,Welsh, Emma J.,Matijssen, Cornelis,Anderson, Victoria E.,Antoni, Laurent,Boxall, Kathy,Urban, Frederique,Hayes, Angela,Raynaud, Florence I.,Rigoreau, Laurent J. M.,Raynham, Tony,Aherne, G. Wynne,Pearl, Laurence H.,Oliver, Antony W.,Garrett, Michelle D.,Collins, Ian
, p. 580 - 590 (2011/03/21)
Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl) phenol 46 (IC50 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).
