1213269-23-8 Usage
Biological Activity
Different sources of media describe the Biological Activity of 1213269-23-8 differently. You can refer to the following data:
1. WZ4002 is a novel, mutant selective EGFR inhibitor. The IC50 is 2 nM/8 nM when it acts on IC50 of 2 nM/8 nM in EGFR (L858R)/(T790M), and it has no inhibitory effect on ERBB2 phosphorylation (T798I).
2. wz4002 is a novel mutant-selective epidermal growth factor receptor (egfr) kinase inhibitor that potently and irreversibly suppresses the atp-dependent auto-phosphorylation of both wild-type egfr and egfr mutants, including egfr dele746_a750/t790m, egfr l858r/t790m, egfr t790m, egfr dele746_a750 and egfr l858r, with inhibition constant ki of 13.6 nm, 1.8 nm, 4 nm, 5 nm, 3.9 nm and 8.5 nm respectively. although wz4002 is actively against egfr mutants rather than wild-type egfr at lower concentrations resulting in less toxicity in normal tissues, wild-type egfr is susceptible to higher concentrations of wz4002 as well as prolonged administration of wz4002, especially in tissues where it accumulates.
In vitro studies
WZ4002 also inhibit other EGFR genotypes. For instance, the IC50 is 2nM and 6nM respectively when it acts on E746_A750 and E746_A750/T790M. Besides, the IC50 is 32nM when it acts on wild-type EGFR. It could inhibit the phosphorylation of EGFR, AKT and ERK1/2 when it acts on non-small cell lung cancer (NSCLC). WZ4002 also could inhibit the phosphorylation of EGFR when it acts on NIH-3T3 cells expressing different EGFRT790M mutant alleles. The dissociation constant of kinase was 95% higher when in the test when WZ4002 involved than that in the test DMSO involved instead. Because in aniline substitution in the C2 WZ4002 could obtain a methoxy group when it acts on EGFR, thus it’s more effective when it acts on EGFR than WZ3146. Compared with the quinazoline inhibitors, the efficiency of WZ4002 is 100 times lower than when it acts on wild-type EGFR. The inhibitory effect of WZ4002 on EGFR kinase activity of recombinant L858R/T790M protein is much higher than restrainable wild-type EGFR’s. However HKI-272 and Gefitinib are happened to have opposite inhibitory effect compared with WZ4002. In addition, phosphorylation of EGFR in H1975 and HCC827 cells of anti-Src TKI could be completely inhibited by third-generation EGFR TKI and WZ4002.
In vivo studies
When treated with T790M mutant mouse model for 2 weeks and had been used to study the efficacy of WZ4002, it is found that treatment with WZ4002 resulted in more effective significant tumor regression compared to the control group. When treated with low dose WZ4002 and high dose WZ4002, it would resulted in a 26% and 36% decrease in average uptake respectively.
Uses
Different sources of media describe the Uses of 1213269-23-8 differently. You can refer to the following data:
1. A novel mutant-selective EGFR kinase inhibitor of EGFRL858R and EGFRL858R/T790M with IC50s of 2 nM and 8 nM, respectively.
2. WZ 4002 is an EGFR phosphorylation inhibitor.
references
[1]lee hj, schaefer g, heffron tp, shao l, ye x, sideris s, malek s, chan e, merchant m, la h, ubhayakar s, yauch rl, pirazzoli v, politi k, settleman j. noncovalent wild-type-sparing inhibitors of egfr t790m. cancer discov. 2013 feb;3(2):168-81. doi: 10.1158/2159-8290.cd-12-0357. epub 2012 dec 10.[2]zhou w, ercan d, chen l, yun ch, li d, capelletti m, cortot ab, chirieac l, iacob re, padera r, engen jr, wong kk, eck mj, gray ns, j?nne pa. novel mutant-selective egfr kinase inhibitors against egfr t790m. nature. 2009 dec 24;462(7276):1070-4. doi: 10.1038/nature08622.[3]zannetti a, iommelli f, speranza a, salvatore m, del vecchio s. 3'-deoxy-3'-18f-fluorothymidine pet/ct to guide therapy with epidermal growth factor receptor antagonists and bcl-xl inhibitors in non-small cell lung cancer. j nucl med. 2012 mar;53(3):443-50. doi: 10.2967/jnumed.111.096503. epub 2012 feb 13.
Check Digit Verification of cas no
The CAS Registry Mumber 1213269-23-8 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,1,3,2,6 and 9 respectively; the second part has 2 digits, 2 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 1213269-23:
(9*1)+(8*2)+(7*1)+(6*3)+(5*2)+(4*6)+(3*9)+(2*2)+(1*3)=118
118 % 10 = 8
So 1213269-23-8 is a valid CAS Registry Number.
InChI:InChI=1S/C25H27ClN6O3/c1-4-23(33)28-17-6-5-7-19(14-17)35-24-20(26)16-27-25(30-24)29-21-9-8-18(15-22(21)34-3)32-12-10-31(2)11-13-32/h4-9,14-16H,1,10-13H2,2-3H3,(H,28,33)(H,27,29,30)
1213269-23-8Relevant articles and documents
Design, synthesis and biological evaluation of WZ4002 analogues as EGFR inhibitors
Romu, Aireen A.,Lei, Zining,Zhou, Bin,Chen, Zhe-Sheng,Korlipara, Vijaya
, p. 4832 - 4837 (2017/10/06)
A series of thirty two anilinopyrimidines derived from WZ4002 has been synthesized and evaluated for percentage inhibition of six different EGFR kinases using LanthaScreen binding assay method (EGFR d746 – 750) or Z'LYTE assay method (EGFR-WT, EGFR d746 – 750, EGFR T790M, EGFR T790M L858R, EGFR C797S and EGFR T790M L858R C797S). Ortho-hydroxyacetamide 10 exhibited complete inhibition of all the six kinases at 10 μM. Against the triple mutant, EGFR T790M C797S L858R, compounds 9–12 exhibited complete inhibition at 10 μM and nearly complete inhibition at 1 μM. The target compounds were also evaluated using the MTT assay to determine their cytotoxic activity against human non-small cell lung cancer cells (PC9, PC9GR and H460) and mouse leukemic cells (Ba/F3 WT and Ba/F3T 3151). Overall, 7, 9–12, 30 and 31 were found to be the most potent compounds across all five cell lines.
Discovery of selective irreversible inhibitors for EGFR-T790M
Zhou, Wenjun,Ercan, Dalia,Jaenne, Pasi A.,Gray, Nathanael S.
, p. 638 - 643 (2011/03/18)
Targeting the epidermal growth factor receptor kinase (EGFR) with ATP-competitive kinase inhibitors results in dramatic but short-lived responses in patients with EGFR mutant non small cell lung cancer. A series of novel covalent EGFR kinase inhibitors with selectivity for the clinically relevant T790M 'gatekeeper' resistance mutation relative to wild-type EGFR were discovered by library screening. A representative compound 3i was obtained through a systematic SAR study guided by mutant EGFR-dependent cellular proliferation assays.
