WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 406106
Description: CL-387785, also known as EKI-785 , is a n irreversible inhibitor of EGF-receptor (EGFR) kinase activity in vivo (IC50 = 250-490 pM). CL-387785 covalently bound to EGF-R. It also specifically inhibited kinase activity of the protein (IC50 = 370+/-120 pM), blocked EGF-stimulated autophosphorylation of the receptor in cells (ic50 approximately 5 nM), inhibited cell proliferation (IC50 = 31-125 nM) primarily in a cytostatic manner in cell lines that overexpress EGF-R or c-erbB-2, and profoundly blocked the growth of a tumor that overexpresses EGF-R in nude mice (when given orally at 80 mg/kg/day for 10 days, daily). CL-387,785 is useful for studying the interaction of small molecules with EGF-R and may have clinical utility.
MedKoo Cat#: 406106
Chemical Formula: C18H13BrN4O
Exact Mass: 380.02727
Molecular Weight: 381.23
Elemental Analysis: C, 56.71; H, 3.44; Br, 20.96; N, 14.70; O, 4.20
Synonym: CL387785; CL 387785; CL-387785; EKI785; EK-I785; EK I785.
IUPAC/Chemical Name: N-[4-[(3-Bromophenyl)amino]-6-quinazolinyl]-2-butynamide
InChi Key: BTYYWOYVBXILOJ-UHFFFAOYSA-N
InChi Code: InChI=1S/C18H13BrN4O/c1-2-4-17(24)22-14-7-8-16-15(10-14)18(21-11-20-16)23-13-6-3-5-12(19)9-13/h3,5-11H,1H3,(H,22,24)(H,20,21,23)
SMILES Code: CC#CC(NC1=CC2=C(NC3=CC=CC(Br)=C3)N=CN=C2C=C1)=O
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
|Biological target:||CL-387785 (EKI-785, WAY-EKI 785) is an irreversible, and selective EGFR inhibitor with IC50 of 370 pM.|
|In vitro activity:||It is shown that higher concentrations of the irreversible EGFR inhibitor CL-387,785 are required to inhibit EGFR phosphorylation in T790M-expressing cells compared with EGFR mutant NSCLC cells without T790M. Additionally, CL-387,785 does not fully suppress phosphorylation of other activated receptor tyrosine kinases (RTK) in T790M-expressing cells. These deficiencies result in residual Akt and mammalian target of rapamycin (mTOR) activities. Full suppression of EGFR-mediated signaling in T790M-expressing cells requires the combination of CL-387,785 and rapamycin. In contrast, Hsp90 inhibition overcomes these limitations in vitro and depletes cells of EGFR, other RTKs, and phospho-Akt and inhibits mTOR signaling whether or not T790M is present. EGFR-T790M-expressing cells rendered resistant to CL-387,785 by a kinase switch mechanism retain sensitivity to Hsp90 inhibition. Finally, Hsp90 inhibition causes regression in murine lung adenocarcinomas driven by mutant EGFR (L858R) with or without T790M. However, efficacy in the L858R-T790M model requires a more intense treatment schedule and responses were transient. Reference: Cancer Res. 2008 Jul 15;68(14):5827-38. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18632637/|
|In vivo activity:||Treatment of BPK mice with EKI-785 resulted in a marked reduction of collecting tubule (CT) cystic lesions, improved renal function, decreased biliary epithelial abnormalities, and an increased life span. Untreated cystic animals died of renal failure at postnatal day 24 (P-24) with a CT cystic index of 4.8, a maximal urine osmolarity of 361 mOsm, and moderate to severe biliary abnormalities. Cystic animals treated with EKI-785 to postnatal day 48 (P-48) were alive and well with normal renal function, a reduced CT cystic index of 2.0 (P < 0.02), a threefold increased in maximum urinary concentrating ability (P < 0.01), and a significant decrease in biliary epithelial proliferation/fibrosis (P < 0.01). Reference: Kidney Int. 2000 Jan;57(1):33-40. https://linkinghub.elsevier.com/retrieve/pii/S0085-2538(15)46703-1|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 381.23 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|
|In vitro protocol:||1. Shimamura T, Li D, Ji H, Haringsma HJ, Liniker E, Borgman CL, Lowell AM, Minami Y, McNamara K, Perera SA, Zaghlul S, Thomas RK, Greulich H, Kobayashi S, Chirieac LR, Padera RF, Kubo S, Takahashi M, Tenen DG, Meyerson M, Wong KK, Shapiro GI. Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance. Cancer Res. 2008 Jul 15;68(14):5827-38. doi: 10.1158/0008-5472.CAN-07-5428. PMID: 18632637; PMCID: PMC3272303. 2. 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. PMID: 22331221.|
|In vivo protocol:||1. Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int. 2000 Jan;57(1):33-40. doi: 10.1046/j.1523-1755.2000.00829.x. PMID: 10620185. 2. 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. PMID: 22331221.|
1: Tomioka H, Mukohara T, Kataoka Y, Ekyalongo RC, Funakoshi Y, Imai Y, Kiyota N, Fujiwara Y, Minami H. Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification. Int J Oncol. 2012 Aug;41(2):551-8. doi: 10.3892/ijo.2012.1485. Epub 2012 May 17. PubMed PMID: 22614071.
2: Chiu HC, Chang TY, Huang CT, Chao YS, Hsu JT. EGFR and myosin II inhibitors cooperate to suppress EGFR-T790M-mutant NSCLC cells. Mol Oncol. 2012 Jun;6(3):299-310. doi: 10.1016/j.molonc.2012.02.001. Epub 2012 Feb 10. PubMed PMID: 22366308.
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. PubMed PMID: 22331221.
4: Kancha RK, von Bubnoff N, Bartosch N, Peschel C, Engh RA, Duyster J. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS One. 2011;6(10):e26760. doi: 10.1371/journal.pone.0026760. Epub 2011 Oct 28. PubMed PMID: 22046346; PubMed Central PMCID: PMC3203921.
5: Hama T, Yuza Y, Suda T, Saito Y, Norizoe C, Kato T, Moriyama H, Urashima M. Functional mutation analysis of EGFR family genes and corresponding lymph node metastases in head and neck squamous cell carcinoma. Clin Exp Metastasis. 2012 Jan;29(1):19-25. doi: 10.1007/s10585-011-9425-5. Epub 2011 Sep 28. PubMed PMID: 21953075.
6: Chung JH, Rho JK, Xu X, Lee JS, Yoon HI, Lee CT, Choi YJ, Kim HR, Kim CH, Lee JC. Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs. Lung Cancer. 2011 Aug;73(2):176-82. doi: 10.1016/j.lungcan.2010.11.011. Epub 2010 Dec 17. PubMed PMID: 21168239.
7: Eisinger DA, Ammer H. Epidermal growth factor treatment switches δ-opioid receptor-stimulated extracellular signal-regulated kinases 1 and 2 signaling from an epidermal growth factor to an insulin-like growth factor-1 receptor-dependent mechanism. Mol Pharmacol. 2011 Feb;79(2):326-35. doi: 10.1124/mol.110.064956. Epub 2010 Nov 15. PubMed PMID: 21078885.
8: Yu Z, Boggon TJ, Kobayashi S, Jin C, Ma PC, Dowlati A, Kern JA, Tenen DG, Halmos B. Resistance to an irreversible epidermal growth factor receptor (EGFR) inhibitor in EGFR-mutant lung cancer reveals novel treatment strategies. Cancer Res. 2007 Nov 1;67(21):10417-27. PubMed PMID: 17974985.
9: Kobayashi S, Shimamura T, Monti S, Steidl U, Hetherington CJ, Lowell AM, Golub T, Meyerson M, Tenen DG, Shapiro GI, Halmos B. Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling. Cancer Res. 2006 Dec 1;66(23):11389-98. PubMed PMID: 17145885.
10: Engelman JA, Mukohara T, Zejnullahu K, Lifshits E, BorrÃ¡s AM, Gale CM, Naumov GN, Yeap BY, Jarrell E, Sun J, Tracy S, Zhao X, Heymach JV, Johnson BE, Cantley LC, JÃ¤nne PA. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006 Oct;116(10):2695-706. Epub 2006 Aug 10. PubMed PMID: 16906227; PubMed Central PMCID: PMC1570180.
11: Greulich H, Chen TH, Feng W, JÃ¤nne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, Meyerson M. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2005 Nov;2(11):e313. Epub 2005 Oct 4. PubMed PMID: 16187797; PubMed Central PMCID: PMC1240052.
12: Kobayashi S, Ji H, Yuza Y, Meyerson M, Wong KK, Tenen DG, Halmos B. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res. 2005 Aug 15;65(16):7096-101. PubMed PMID: 16103058.
13: Desai AA, Ratain MJ. EGFR pharmacogenomics: the story continues to mutate and evolve. Am J Pharmacogenomics. 2005;5(2):137-9. PubMed PMID: 15813677.
14: Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int. 2000 Jan;57(1):33-40. PubMed PMID: 10620185.
15: Sweeney WE, Futey L, Frost P, Avner ED. In vitro modulation of cyst formation by a novel tyrosine kinase inhibitor. Kidney Int. 1999 Aug;56(2):406-13. PubMed PMID: 10432378.
16: Discafani CM, Carroll ML, Floyd MB Jr, Hollander IJ, Husain Z, Johnson BD, Kitchen D, May MK, Malo MS, Minnick AA Jr, Nilakantan R, Shen R, Wang YF, Wissner A, Greenberger LM. Irreversible inhibition of epidermal growth factor receptor tyrosine kinase with in vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785). Biochem Pharmacol. 1999 Apr 15;57(8):917-25. PubMed PMID: 10086326.