Biological Activity
nvp-aew541 is a novel, potent and selective inhibitor of igf-ir kinase with ic50 value of 0.086 μm [1].nvp-aew541 is a pyrrolo(2,3-d) pyrimidine derivative. it has been reported to abolish igf-i-induced igf-ir autophosphorylation and to block the igf-ir signaling pathway mainly in ecc-1 and uspc-1 cancer cells. also in these cell lines, nvp-aew541 has been shown to change the igf-i induced cell cycle and to lead apoptotic cell death as well as exhibit antiproliferative effects [2]. in addition, it is observed that nvp-aew541 can induce radiosensitization in pten wild-type cell lines [3].
Biochem/physiol Actions
NVP-AEW541 is a reversible, ATP-competitive, orally available insulin-like growth factor-I receptor (IGF-IR, IGF-1R) inhibitor that, despite its equipotency against recombinant kinase domains of insulin receptor (InsR) and IGF-IR in cell-free kinase assays (IC50 = 140 & 150 nM, respectively), exhibits high selectivity toward cellular autophosphorylation of endogenous full-length IGF-1R (IC50 = 86 nM) over InsR (IC50 = 2.3 μM), HER1, PDGFR, c-Kit, and Bcr-Abl p210 (IC50 >5 μM). AEW541 effectively inhibits IGF-IR-mediated signaling and cancer survival (IC50 = 105 nM/MCF-7 soft agar growth, 1.64 μM/NWT-21 proliferation) in cultures and tumor growth in vivo (20 to 50 mg/kg twice daily p.o.; NWT-21 fibrosarcoma & TC-71 musculoskeletal sarcoma xenografts in mice).
References
[1] carlos garc a-echeverr a, mark a. pearson, andreas marti, thomas meyer, juergen mestan, johann zimmermann, jiaping gao, josef brueggen, hans-georg capraro, robert cozens, dean b. evans, doriano fabbro, pascal furet, diana graus porta, janis liebetanz, georg martiny-baron, stephan ruetz, and francesco hofmann. in vivo antitumor activity of nvp-aew541—a novel, potent, and selective inhibitor of the igf-ir kinase. cancer cell.2004 mar (5):231-239.
[2] zohar attias-geva, itay bentov, ami fishman, haim werner, ilan bruchim. insulin-like growth factor-i receptor inhibition by speci c tyrosine kinase inhibitor nvp-aew541 in endometrioid and serous papillary endometrial cancer cell lines. gynecologic oncology. 2011 feb (121):383-389.
[3] sofie f. isebaert, johannes v. swinnen, william h. mcbride, and karin m. haustermans. insulin-like growth factor–type 1 receptor inhibitor nvp-aew541 enhances radiosensitivity of pten wild-type but not pten-deficient human prostate cancer cells. international journal of radiation oncology biology physics. 2011 (81):239-247.
