Identification of Methionine Aminopeptidase-2 (MetAP-2) Inhibitor M8891: 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 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.

Targeting methionine aminopeptidase 2 in cancer, obesity, and autoimmunity

“…Although none of these inhibitors has yet reached the market, continued promising preclinical and clinical efficacy results for MetAP2i over the years have retained the interest of the drug development community. Recently, Merck KGaA published the first reversible clinical candidate targeting MetAP2 [14], indicating that the field of MetAP2i remains vibrant and of high interest.…”

“…This compound, based on a cyclic tartronic diamide scaffold, was found to be active only after a spontaneous oxidation event during storage, and further isolation of the S-enantiomer and subsequent optimization steps led to compound 11 with potent antiproliferative activity in HUVECs, favourable pharmacokinetic characteristics, and robust antitumour activity in a murine glioblastoma model [13]. Efforts to prevent the enterohepatic circulation liability of 11 while maintaining potency led to clinical compound M8891 (12), which is currently in Phase I trials [14].…”

“…However, inhibiting both enzymes responsible for N-terminal methionine excision, which is an essential process in all organisms [77], was a risky approach, and this strategy was not pursued further. Recently, Merck KGaA published the first specific and reversible MetAP2 clinical candidate, which entered Phase I trials [14]; the future progress of this compound is a test case for the potential of reversible MetAP2i. Finally, it is interesting to note that the earliest examples of proteolysis targeting chimeras (PROTACs) were developed against MetAP2 [78]; novel applications may arise from next-generation MetAP2targeted PROTACs since they would also target the scaffolding functions of MetAP2 and thereby phenocopy MetAP2 knockdown or knockout [79].…”

“…The natural compounds fumagillin (1) and ovalicin (3), the semisynthetic analogues TNP-470 (2)[1] and PPI-2458 (4)[9], and the more drug-like spiroepoxytriazole (5)[38]. The dual MetAP1/MetAP2 reversible inhibitor LAF389 (6)[4], A-357300 bestatin-like compound (7)[5], anthranilic acid sulfonamide A-800141 (8)[8], triazole (9)[7], triazolo pyrimidine (10)[12], cyclic tartronic acid(11) [13], and M8891 clinical compound from Merck KGaA (12)[14]. Second-generation fumagillin derivatives…”

Med Chem Remote: The Frontiers in Medicinal Chemistry 2021

“…The importance of covalent binders as drugs but also as chemical tools were pointed out by the second speaker of the session, Rob Liskamp (Glasgow University). He described the development and synthesis of peptido sulfonylfluorides and peptido thiosulfonates as potential proteasome [33,34] and (brain) prolyl oligopeptidase (POP) inhibitors [35] …”