WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 203170
Description: WZ4002 is EGFR inhibitor against EGFR T790M (mutation of the gatekeeper T790 residue) which is detected in 50% of clinically resistant patients to gefitinib or erlotinib. WZ4002 has a basic chemical framework (covalent pyrimidine) which is different from that of other EGFR inhibitors. This agent is 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wildtype EGFR, than quinazoline-based EGFR inhibitors (HKI-272 and CL-387,785) in vitro.
MedKoo Cat#: 203170
Chemical Formula: C25H27ClN6O3
Exact Mass: 494.18332
Molecular Weight: 494.97
Elemental Analysis: C, 60.66; H, 5.50; Cl, 7.16; N, 16.98; O, 9.70
Synonym: WZ4002; WZ-4002; WZ 4002.
IUPAC/Chemical Name: N-(3-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide
InChi Key: ITTRLTNMFYIYPA-UHFFFAOYSA-N
InChi Code: 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)
SMILES Code: C=CC(NC1=CC=CC(OC2=NC(NC3=CC=C(N4CCN(C)CC4)C=C3OC)=NC=C2Cl)=C1)=O
Appearance: White to beige 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
|Biological target:||WZ4002 is an EGFR inhibitor with IC50s of 2, 8, 3 and 2 nM for EGFRL858R, EGFRL858R/T790M, EGFRE746_A750 and EGFRE746_A750/T790M, respectively.|
|In vitro activity:||The ability of combination treatment with WZ4002 and SAHA to inhibit the proliferation of human NSCLC (non-small cell lung cancer) cells with an EGFR T790M mutation was investigated. While treatment with WZ4002 alone reduced the viability of PC-9G and H1975 cells in a small amount, combining it with SAHA resulted in significantly decreased cell viability for both cell lines (Fig. 1a, top panel). The combination of SAHA and WZ4002 manifested a synergistic effect on the viability of both PC-9G and H1975 cells in most combination concentrations (Fig. 1a, bottom panel). Reference: Int J Cancer. 2015 Jun 1;136(11):2717-29. https://onlinelibrary.wiley.com/doi/10.1002/ijc.29320|
|In vivo activity:||It was investigated whether combined treatment with SAHA and WZ4002 might show an enhanced anti-tumor effect on xenografts of H1975 cells in vivo. Following tumor formation, nude mice were treated with gefitinib (50 mg/kg), SAHA (25 mg/kg), or WZ4002 (25 mg/kg) alone or together with SAHA for 3 weeks. Monotherapy with gefitinib or WZ4002 resulted in only a marginal decrease in tumor volume, whereas treatment with the combination of WZ4002 and SAHA led to a marked shrinkage of tumor (Fig. 5a). Reference: Int J Cancer. 2015 Jun 1;136(11):2717-29. https://onlinelibrary.wiley.com/doi/10.1002/ijc.29320|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 494.97 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|
|Formulation protocol:||1. Lee TG, Jeong EH, Kim SY, Kim HR, Kim CH. The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. Int J Cancer. 2015 Jun 1;136(11):2717-29. doi: 10.1002/ijc.29320. Epub 2014 Nov 26. PMID: 25382705.|
|In vitro protocol:||1. Lee TG, Jeong EH, Kim SY, Kim HR, Kim CH. The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. Int J Cancer. 2015 Jun 1;136(11):2717-29. doi: 10.1002/ijc.29320. Epub 2014 Nov 26. PMID: 25382705.|
|In vivo protocol:||1. Lee TG, Jeong EH, Kim SY, Kim HR, Kim CH. The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. Int J Cancer. 2015 Jun 1;136(11):2717-29. doi: 10.1002/ijc.29320. Epub 2014 Nov 26. PMID: 25382705.|
1: Roskoski R Jr. ErbB/HER protein-tyrosine kinases: Structures and small molecule inhibitors. Pharmacol Res. 2014 Sep;87C:42-59. doi: 10.1016/j.phrs.2014.06.001. Epub 2014 Jun 11. Review. PubMed PMID: 24928736.
2: Nanjo S, Yamada T, Nishihara H, Takeuchi S, Sano T, Nakagawa T, Ishikawa D, Zhao L, Ebi H, Yasumoto K, Matsumoto K, Yano S. Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. PLoS One. 2013 Dec 26;8(12):e84700. doi: 10.1371/journal.pone.0084700. eCollection 2013. PubMed PMID: 24386407; PubMed Central PMCID: PMC3873434.
3: Yano S, Nakagawa T. The current state of molecularly targeted drugs targeting HGF/Met. Jpn J Clin Oncol. 2014 Jan;44(1):9-12. doi: 10.1093/jjco/hyt188. Epub 2013 Dec 25. PubMed PMID: 24371262.
4: Han C, Huang Z, Zheng C, Wan L, Lai Y, Peng S, Ding K, Ji H, Zhang Y. Nitric oxide donating anilinopyrimidines: synthesis and biological evaluation as EGFR inhibitors. Eur J Med Chem. 2013 Aug;66:82-90. doi: 10.1016/j.ejmech.2013.05.026. Epub 2013 May 29. PubMed PMID: 23792318.
5: Han C, Huang Z, Zheng C, Wan L, Zhang L, Peng S, Ding K, Ji H, Tian J, Zhang Y. Novel hybrids of (phenylsulfonyl)furoxan and anilinopyrimidine as potent and selective epidermal growth factor receptor inhibitors for intervention of non-small-cell lung cancer. J Med Chem. 2013 Jun 13;56(11):4738-48. doi: 10.1021/jm400463q. Epub 2013 May 24. PubMed PMID: 23668441.
6: 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. PubMed PMID: 23229345; PubMed Central PMCID: PMC3576842.
7: Cortot AB, Repellin CE, Shimamura T, Capelletti M, Zejnullahu K, Ercan D, Christensen JG, Wong KK, Gray NS, JÃ¤nne PA. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res. 2013 Jan 15;73(2):834-43. doi: 10.1158/0008-5472.CAN-12-2066. Epub 2012 Nov 19. PubMed PMID: 23172312; PubMed Central PMCID: PMC3994895.
8: Ercan D, Xu C, Yanagita M, Monast CS, Pratilas CA, Montero J, Butaney M, Shimamura T, Sholl L, Ivanova EV, Tadi M, Rogers A, Repellin C, Capelletti M, Maertens O, Goetz EM, Letai A, Garraway LA, Lazzara MJ, Rosen N, Gray NS, Wong KK, JÃ¤nne PA. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov. 2012 Oct;2(10):934-47. doi: 10.1158/2159-8290.CD-12-0103. Epub 2012 Sep 7. PubMed PMID: 22961667; PubMed Central PMCID: PMC3477553.
9: Nakagawa T, Takeuchi S, Yamada T, Nanjo S, Ishikawa D, Sano T, Kita K, Nakamura T, Matsumoto K, Suda K, Mitsudomi T, Sekido Y, Uenaka T, Yano S. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Mol Cancer Ther. 2012 Oct;11(10):2149-57. doi: 10.1158/1535-7163.MCT-12-0195. Epub 2012 Jul 25. PubMed PMID: 22844075.
10: Sakuma Y, Yamazaki Y, Nakamura Y, Yoshihara M, Matsukuma S, Koizume S, Miyagi Y. NF-κB signaling is activated and confers resistance to apoptosis in three-dimensionally cultured EGFR-mutant lung adenocarcinoma cells. Biochem Biophys Res Commun. 2012 Jul 13;423(4):667-71. doi: 10.1016/j.bbrc.2012.06.009. Epub 2012 Jun 10. PubMed PMID: 22695117.
WZ4002 is one of three new compounds designed specifically to bind to and inhibit T790M-mutated EGFR. Importantly, WZ4002 does not inhibit wild-type EGFR; thus, it may have less effect on normal body cells and not cause diarrhea or rash like iressa and tarceva. WZ4002 is a compound that can inhibit T790M EGFR in the laboratory cells without inhibiting normal EGFR. Clinically effective doses could be safely reached in the mice. This new compound seems sufficiently promising in the lab to move on to phase I testing. However, as of August 2010, no news about clinical study was reported in the internet.
Researchers tested WZ4002 in NSCLC cells with EGFR T90M and found several that were up to 100 times more potent than quinazolines in restricting cell growth. As an unexpected bonus, these compounds were nearly 100 times less powerful at slowing the growth of cells with normal EGFR, suggesting they would be less likely to produce side effects than current drugs. The agent which performed the best is the pyrimidine WZ4002. (source: http://lcins.org/2009/12/egfr-and-wz4002/).