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Identification of Methionine Aminopeptidase-2 (MetAP-2) Inhibitor M8891: A Clinical Compound for the Treatment of Cancer
- Source :
- Journal of Medicinal Chemistry. 62:11119-11134
- Publication Year :
- 2019
- Publisher :
- American Chemical Society (ACS), 2019.
-
Abstract
- The recently disclosed next generation of reversible, selective, and potent MetAP-2 inhibitors introduced a cyclic tartronic diamide scaffold. However, the lead compound 1a suffered from enterohepatic circulation, preventing further development. Nevertheless, 1a served as a starting point for further optimization. Maintaining potent antiproliferation activity, while improving other compound properties, enabled the generation of an attractive array of new MetAP-2 inhibitors. The most promising derivatives were identified by a multiparameter analysis of the compound properties. Essential for the efficient selection of candidates with in vivo activity was the identification of molecules with a long residence time on the target protein, high permeability, and low efflux ratio not only in Caco-2 but also in the MDR-MDCK cell line. Orally bioavailable, potent, and reversible MetAP-2 inhibitors impede the growth of primary endothelial cells and demonstrated antitumoral activity in mouse models. This assessment led to the nomination of the clinical development compound M8891, which is currently in phase I clinical testing in oncology patients.
- Subjects :
- A549 cell
0303 health sciences
Chemistry
Cell growth
Pharmacology
01 natural sciences
METAP2
0104 chemical sciences
010404 medicinal & biomolecular chemistry
03 medical and health sciences
chemistry.chemical_compound
In vivo
Drug Discovery
Molecular Medicine
Structure–activity relationship
Target protein
Efflux
Lead compound
030304 developmental biology
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi...........539fb7d602f3d1bbfe1d4a86e7331eb7