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Eur J Med Chem. 2015 May 5;95:526-45. doi: 10.1016/j.ejmech.2015.03.055. Epub 2015 Mar 25.

Structure-activity relationship and properties optimization of a series of quinazoline-2,4-diones as inhibitors of the canonical Wnt pathway.

Author information

1
Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. Electronic address: arianna.nencini@gmail.com.
2
Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
3
Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Aptuit S.r.l., Via Alessandro Fleming 4, 37135 Verona, Italy.
4
Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Children's Tumor Foundation, 95 Pine Street, 16th Floor, New York, 10005 NY, USA.
5
Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Tespharma s.r.l., Taverne di Corciano 20, Perugia, Italy.
6
Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Novartis Vaccines, Via Fiorentina, 53100 Siena, Italy.
7
Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Merck KgaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
8
Sienabiotech S.p.A., Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Glaxo Smith Kline Neural Pathways DPU, 11 Biopolis Way, The Helios, 03-01/02, Singapore 138667, Singapore.

Abstract

Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.

KEYWORDS:

Glioblastoma; Small molecule; Structure–activity relationship; Wnt pathway; β-catenin

PMID:
25847770
DOI:
10.1016/j.ejmech.2015.03.055
[Indexed for MEDLINE]

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