KRN633
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MedKoo CAT#: 406288

CAS#: 286370-15-8

Description: KRN633 is a potent and selective VEGFR inhibitor. which inhibits tyrosine phosphorylation of VEGFR-2 (IC50 = 1.16 nmol/L) in human umbilical vein endothelial cells. Selectivity profiling with recombinant tyrosine kinases showed that KRN633 is highly selective for VEGFR-1, -2, and -3. KRN633 inhibits tumor growth in several in vivo tumor xenograft models with diverse tissue origins, including lung, colon, and prostate, in athymic mice and rats. KRN633 also causes the regression of some well-established tumors and those that had regrown after the cessation of treatment. KRN633 was well tolerated and had no significant effects on body weight or the general health of the animals. KRN633 might be useful in the treatment of solid tumors and other diseases that depend on pathologic angiogenesis. ( Mol Cancer Ther. 2004 Dec;3(12):1639-49 )


Chemical Structure

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KRN633
CAS# 286370-15-8

Theoretical Analysis

MedKoo Cat#: 406288
Name: KRN633
CAS#: 286370-15-8
Chemical Formula: C20H21ClN4O4
Exact Mass: 416.12513
Molecular Weight: 416.86
Elemental Analysis: C, 57.62; H, 5.08; Cl, 8.50; N, 13.44; O, 15.35

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Same day
50.0mg USD 250.0 Same day
100.0mg USD 450.0 Same day
200.0mg USD 750.0 Same day
500.0mg USD 1250.0 Same day
1.0g USD 1950.0 Same day
2.0g USD 3250.0 Same day
5.0g USD 5250.0 2 Weeks
10.0g USD 8950.0 2 Weeks
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Synonym: KRN633; KRN-633; KRN 633.

IUPAC/Chemical Name: 1-(2-chloro-4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-propylurea

InChi Key: VPBYZLCHOKSGRX-UHFFFAOYSA-N

InChi Code: InChI=1S/C20H21ClN4O4/c1-4-7-22-20(26)25-15-6-5-12(8-14(15)21)29-19-13-9-17(27-2)18(28-3)10-16(13)23-11-24-19/h5-6,8-11H,4,7H2,1-3H3,(H2,22,25,26)

SMILES Code: O=C(NCCC)NC1=CC=C(OC2=C3C=C(OC)C(OC)=CC3=NC=N2)C=C1Cl

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: KRN-633 is a potent VEGFR inhibitor with IC50s of 170, 160 and 125 nM for VEGFR1, VEGFR2 and VEGFR3, respectively.
In vitro activity: To investigate the effect of KRN633 on in vitro tube formation by endothelial cells, HUVECs were cocultured with fibroblasts in the presence of KRN633. The formation of capillary-like structures induced by 10 ng/mL VEGF was inhibited by KRN633 (Fig. 3A). The average area of the tubes, cell overcrowding, total length of the tubes, and number of capillary connections and paths per field were measured (Fig. 3B). There was limited formation of capillary-like structures without VEGF stimulation. VEGF increased the average area, total tube length, number of capillary connections, and number of paths per field by 2.9-, 3.4-, 39-, and 7.4-fold, respectively. KRN633 at a concentration of 3 nmol/L approximately halved the increase in the number of capillary connections and paths. At a concentration of 10 nmol/L, it also inhibited the increase in average area and total tube length by ∼50%. At a concentration of 30 nmol/L or more, the parameters of tube formation were reduced to below their basal levels. These findings suggest that KRN633 can block survival signaling by VEGF and trigger the apoptosis of HUVECs at sufficiently high concentrations. Reference: Mol Cancer Ther. 2004 Dec;3(12):1639-49. https://mct.aacrjournals.org/content/3/12/1639.long
In vivo activity: The effect of KRN633 on well-established tumor xenografts in athymic mice (initial tumor volume, 500–667 mm3) was also examined. Treatment with KRN633 was initiated when A549, HT29, and Du145 tumors reached an average size of∼500 to 700 mm3. Twice-daily administration of KRN633 at 100 mg/kg induced ∼90% growth inhibition of HT29 tumors and caused the regression of A549 and Du145 tumors by ∼35% and 60%, respectively (Table 2B). The antitumor effect in each established tumor model was superior to that in the corresponding standard (less well established) tumor model. This suggests that the antitumor activity of KRN633 is less affected by initial tumor size. In the periodic intermittent-dosing model, the resumption of treatment led to the regression of DU145 tumors that had regrown after treatment had ceased; this indicates that tumors are less likely to acquire resistance to KRN633 (Fig. 4). The effect of KRN633 on tumor growth was also evaluated in athymic rat xenograft models. Once-daily p.o. administration of KRN633 for 14 days inhibited tumor growth in rats as well as mice. Twice-daily administration of KRN633 had a stronger effect on A549 tumor growth than once-daily administration at the same total dose. KRN633 was well tolerated in all of the in vivo experiments and had no significant effects on the body weight or general health of the animals. Reference: Mol Cancer Ther. 2004 Dec;3(12):1639-49. https://mct.aacrjournals.org/content/3/12/1639.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 11.5 27.59

Preparing Stock Solutions

The following data is based on the product molecular weight 416.86 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.

Recalculate based on batch purity %
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. Nakamura K, Yamamoto A, Kamishohara M, Takahashi K, Taguchi E, Miura T, Kubo K, Shibuya M, Isoe T. KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth. Mol Cancer Ther. 2004 Dec;3(12):1639-49. PMID: 15634658. 2. Sassoli C, Pini A, Chellini F, Mazzanti B, Nistri S, Nosi D, Saccardi R, Quercioli F, Zecchi-Orlandini S, Formigli L. Bone marrow mesenchymal stromal cells stimulate skeletal myoblast proliferation through the paracrine release of VEGF. PLoS One. 2012;7(7):e37512. doi: 10.1371/journal.pone.0037512. Epub 2012 Jul 16. PMID: 22815682; PMCID: PMC3398011. 3. Morita A, Sawada S, Mori A, Arima S, Sakamoto K, Nagamitsu T, Nakahara T. Establishment of an abnormal vascular patterning model in the mouse retina. J Pharmacol Sci. 2018 Apr;136(4):177-188. doi: 10.1016/j.jphs.2018.03.002. Epub 2018 Mar 14. PMID: 29627228
In vitro protocol: 1. Nakamura K, Yamamoto A, Kamishohara M, Takahashi K, Taguchi E, Miura T, Kubo K, Shibuya M, Isoe T. KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth. Mol Cancer Ther. 2004 Dec;3(12):1639-49. PMID: 15634658. 2. Sassoli C, Pini A, Chellini F, Mazzanti B, Nistri S, Nosi D, Saccardi R, Quercioli F, Zecchi-Orlandini S, Formigli L. Bone marrow mesenchymal stromal cells stimulate skeletal myoblast proliferation through the paracrine release of VEGF. PLoS One. 2012;7(7):e37512. doi: 10.1371/journal.pone.0037512. Epub 2012 Jul 16. PMID: 22815682; PMCID: PMC3398011.
In vivo protocol: 1. Morita A, Sawada S, Mori A, Arima S, Sakamoto K, Nagamitsu T, Nakahara T. Establishment of an abnormal vascular patterning model in the mouse retina. J Pharmacol Sci. 2018 Apr;136(4):177-188. doi: 10.1016/j.jphs.2018.03.002. Epub 2018 Mar 14. PMID: 29627228 2. Nakamura K, Yamamoto A, Kamishohara M, Takahashi K, Taguchi E, Miura T, Kubo K, Shibuya M, Isoe T. KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth. Mol Cancer Ther. 2004 Dec;3(12):1639-49. PMID: 15634658.

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1: Asano D, Nakahara T, Mori A, Sakamoto K, Ishii K. Regression of retinal capillaries following N-methyl-D-aspartate-induced neurotoxicity in the neonatal rat retina. J Neurosci Res. 2014 Oct 3. doi: 10.1002/jnr.23492. [Epub ahead of print] PubMed PMID: 25284371.

2: Morita A, Nakahara T, Abe N, Kurauchi Y, Mori A, Sakamoto K, Nagamitsu T, Ishii K. Treatment of mid-pregnant mice with KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces abnormal retinal vascular patterning in their newborn pups. Birth Defects Res B Dev Reprod Toxicol. 2014 Aug;101(4):293-9. doi: 10.1002/bdrb.21112. Epub 2014 May 15. PubMed PMID: 24831925.

3: Morita A, Nakahara T, Abe N, Kurauchi Y, Mori A, Sakamoto K, Nagamitsu T, Ishii K. Effects of pre- and post-natal treatment with KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, on retinal vascular development and patterning in mice. Exp Eye Res. 2014 Mar;120:127-37. doi: 10.1016/j.exer.2014.01.009. Epub 2014 Jan 23. PubMed PMID: 24462631.

4: Abe N, Nakahara T, Morita A, Wada Y, Mori A, Sakamoto K, Nagamitsu T, Ishii K. KRN633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces intrauterine growth restriction in mice. Birth Defects Res B Dev Reprod Toxicol. 2013 Aug;98(4):297-303. doi: 10.1002/bdrb.21064. Epub 2013 Jun 18. PubMed PMID: 23780833.

5: Wada Y, Ozaki H, Abe N, Mori A, Sakamoto K, Nagamitsu T, Nakahara T, Ishii K. Role of vascular endothelial growth factor in maintenance of pregnancy in mice. Endocrinology. 2013 Feb;154(2):900-10. doi: 10.1210/en.2012-1967. Epub 2013 Jan 10. PubMed PMID: 23307787.

6: Sassoli C, Pini A, Chellini F, Mazzanti B, Nistri S, Nosi D, Saccardi R, Quercioli F, Zecchi-Orlandini S, Formigli L. Bone marrow mesenchymal stromal cells stimulate skeletal myoblast proliferation through the paracrine release of VEGF. PLoS One. 2012;7(7):e37512. doi: 10.1371/journal.pone.0037512. Epub 2012 Jul 16. PubMed PMID: 22815682; PubMed Central PMCID: PMC3398011.

7: Loganathan S, Kanteti R, Siddiqui SS, El-Hashani E, Tretiakova M, Vigneswaran H, Cervantes G, Natarajan V, Husain AN, Vokes EE, Kindler HL, Salgia R. Role of protein kinase C β and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism. J Carcinog. 2011 Mar 3;10:4. doi: 10.4103/1477-3163.77274. PubMed PMID: 21383961; PubMed Central PMCID: PMC3049271.

8: Hah YS, Jun JS, Lee SG, Park BW, Kim DR, Kim UK, Kim JR, Byun JH. Vascular endothelial growth factor stimulates osteoblastic differentiation of cultured human periosteal-derived cells expressing vascular endothelial growth factor receptors. Mol Biol Rep. 2011 Feb;38(2):1443-50. doi: 10.1007/s11033-010-0249-1. Epub 2010 Sep 15. PubMed PMID: 20842453.

9: Ban HS, Uno M, Nakamura H. Suppression of hypoxia-induced HIF-1alpha accumulation by VEGFR inhibitors: Different profiles of AAL993 versus SU5416 and KRN633. Cancer Lett. 2010 Oct 1;296(1):17-26. doi: 10.1016/j.canlet.2010.03.010. Epub 2010 Apr 7. PubMed PMID: 20378243.

10: Wada Y, Ozaki H, Abe N, Nagamitsu T, Ohta H, Nakahara T, Ishii K. Effects of KRN633, an inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase, on vascular development of placenta and fetus of mid-pregnancy in mice. J Pharmacol Sci. 2010;112(3):290-8. Epub 2010 Mar 2. PubMed PMID: 20197639.

11: Lee MJ, Song HY, Kim MR, Sung SM, Jung JS, Kim JH. Oncostatin M stimulates expression of stromal-derived factor-1 in human mesenchymal stem cells. Int J Biochem Cell Biol. 2007;39(3):650-9. Epub 2006 Nov 23. PubMed PMID: 17169599.

12: Matsunaga N, Nakamura K, Yamamoto A, Taguchi E, Tsunoda H, Takahashi K. Improvement by solid dispersion of the bioavailability of KRN633, a selective inhibitor of VEGF receptor-2 tyrosine kinase, and identification of its potential therapeutic window. Mol Cancer Ther. 2006 Jan;5(1):80-8. PubMed PMID: 16432165.

13: Nakamura K, Yamamoto A, Kamishohara M, Takahashi K, Taguchi E, Miura T, Kubo K, Shibuya M, Isoe T. KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth. Mol Cancer Ther. 2004 Dec;3(12):1639-49. PubMed PMID: 15634658.

KRN633

25.0mg / USD 150.0


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