Full circle in this thread, MetAP-2 inhibitors back to cancer (think zfgn)......
J Med Chem. 2019 Nov 14. doi: 10.1021/acs.jmedchem.9b01070. [Epub ahead of print]
Identification of Methionine Aminopeptidase-2 (MetAP-2) inhibitor M8891, a Clinical Compound for the Treatment of Cancer.
Heinrich T, Seenisamy J, Becker F, Blume B, Bomke J, Dietz M, Eckert U, Friese-Hamim M, Gunera J, Hansen K, Leuthner B, Musil D, Pfalzgraf J, Rohdich F, Siegl C, Spuck D, Wegener A, Zenke FT.
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 was used as starting point for further optimization. Maintaining potent anti-proliferation activity while improving other compound properties enabled the generation of an attractive array of new MetAP-2 inhibitors. Identification of the most promising derivatives was driven by a multiparameter analysis of the compound properties. High affinity, long residence time, high permeability and low efflux ratio not only in Caco-2 but also in the MDR-MDCK cell line was key for selection of candidates for in vivo efficacy evaluations. Orally bioavailable, potent, and reversible MetAP-2 inhibitors impede growth of primary endothelial cells and demonstrated antitumoral activity in mouse models. This assessment led to nomination of the clinical development compound M8891 which is currently in Phase I clinical testing in oncology patients.
*************************************************
and here's the phase I trial.......
clinicaltrials.gov |
