AEE788

AEE788
Identifiers
	IUPAC name 6-[4-[(4-Ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;
CAS Number	497839-62-0 ;
PubChem CID	10297043;
IUPHAR/BPS	7643;
ChemSpider	8472511 ;
UNII	F9JLR95I3I;
ChEMBL	ChEMBL587723 ;
CompTox Dashboard (EPA)	DTXSID90964400 ;
Chemical and physical data
Formula	C27H32N6
Molar mass	440.595 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCN1CCN(CC1)CC2=CC=C(C=C2)C3=CC4=C(N3)N=CN=C4N[C@H](C)C5=CC=CC=C5;
	InChI InChI=1S/C27H32N6/c1-3-32-13-15-33(16-14-32)18-21-9-11-23(12-10-21)25-17-24-26(28-19-29-27(24)31-25)30-20(2)22-7-5-4-6-8-22/h4-12,17,19-20H,3,13-16,18H2,1-2H3,(H2,28,29,30,31)/t20-/m1/s1 ; Key:OONFNUWBHFSNBT-HXUWFJFHSA-N ;
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AEE788 is a multitargeted human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2 receptor family tyrosine kinases inhibitor with IC₅₀ of 2, 6, 77, 59 nM for EGFR, ErbB2, KDR, and Flt-1.[1] In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited with IC₅₀s of 11 and 220 nM, respectively. It efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. It also inhibits VEGF-induced angiogenesis in a murine implant model. It has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters.[2][3]

The IC50 value of AEE788 against of different kinases

Kinase	IC₅₀(nM)
EGFR ICD	2
ErbB2(HER-2)	6
ErbB4 (HER-4)	160
KDR	77
Tek	2100
IGF1-R	>10000
Ins-R	>10000
PDGFR-beta	320
c-Met	2900
c-Abl	52
c-Src	61
c-Kit	790
RET	740
c-Fms	60
Flt-1	59
Flt-3	730
Flt-4	330
Cdk1/Cyc.B	8000
PKC-alpha	>10000
c-Raf-1	2800
PKA	>10000

The data of antiproliferative activity of AEE788

Cell line	IC₅₀(nM)
NCI-H596	78
MK	56
BT-474	49
SK-BR-3	381
32D/EGFR	300
32D/EGFRvIII	10
MCF-7	2500
MCF-7/EGFRvIII	<5000
T24	4526

References

Traxler P, Allegrini PR, Brandt R, Brueggen J, Cozens R, Fabbro D, Grosios K, Lane HA, McSheehy P, Mestan J, Meyer T, Tang C, Wartmann M, Wood J, Caravatti G (Jul 2004). "AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity". Cancer Res. 64 (14): 4931–41. doi:10.1158/0008-5472.CAN-03-3681. PMID 15256466.
Juengel E, Engler J, Natsheh I, Jones J, Mickuckyte A, Hudak L, Jonas D, Blaheta RA (May 2009). "Combining the receptor tyrosine kinase inhibitor AEE788 and the mammalian target of rapamycin (mTOR) inhibitor RAD001 strongly inhibits adhesion and growth of renal cell carcinoma cells". BMC Cancer. 9 (161): 161. doi:10.1186/1471-2407-9-161. PMC 2693528. PMID 19473483.
Meco D, Servidei T, Zannoni GF, Martinelli E, Prisco MG, de Waure C, Riccardi R (Oct 2010). "Dual Inhibitor AEE788 Reduces Tumor Growth in Preclinical Models of Medulloblastoma". Transl Oncol. 3 (5): 326–35. PMC 2935636. PMID 20885895.

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[pmid15256466-1] Traxler P, Allegrini PR, Brandt R, Brueggen J, Cozens R, Fabbro D, Grosios K, Lane HA, McSheehy P, Mestan J, Meyer T, Tang C, Wartmann M, Wood J, Caravatti G (Jul 2004). "AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity". Cancer Res. 64 (14): 4931–41. doi:10.1158/0008-5472.CAN-03-3681. PMID 15256466.

[pmid19473483-2] Juengel E, Engler J, Natsheh I, Jones J, Mickuckyte A, Hudak L, Jonas D, Blaheta RA (May 2009). "Combining the receptor tyrosine kinase inhibitor AEE788 and the mammalian target of rapamycin (mTOR) inhibitor RAD001 strongly inhibits adhesion and growth of renal cell carcinoma cells". BMC Cancer. 9 (161): 161. doi:10.1186/1471-2407-9-161. PMC 2693528. PMID 19473483.

[pmid20885895-3] Meco D, Servidei T, Zannoni GF, Martinelli E, Prisco MG, de Waure C, Riccardi R (Oct 2010). "Dual Inhibitor AEE788 Reduces Tumor Growth in Preclinical Models of Medulloblastoma". Transl Oncol. 3 (5): 326–35. PMC 2935636. PMID 20885895.