Identification of Methionine Aminopeptidase-2 (MetAP-2) Inhibitor <b>M8891</b>: A Clinical Compound for the Treatment of Cancer

Abstract

The recently disclosed next generation of reversible, selective, and potent MetAP-2 inhibitors introduced a cyclic tartronic diamide scaffold. However, the lead compound <b>1a</b> suffered from enterohepatic circulation, preventing further development. Nevertheless, <b>1a</b> 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 <b>M8891</b>, which is currently in phase I clinical testing in oncology patients.