Charles M. Cook

Carbamate Analogues of Fumagillin as Potent, Targeted Inhibitors of Methionine Aminopeptidase-2

Inhibition of methionine aminopeptidase-2 (MetAP2) represents a novel approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this compound class. Two-step elaboration of fumagillol with amines yielded a diverse series of carbamates at C6 of the cyclohexane spiroepoxide. The most potent of these compounds exhibited subnanomolar inhibition of cell proliferation in HUVEC and BAEC assays. Although a range of functionalities were tolerated at this position, alpha-trisubstituted amines possessed markedly decreased inhibitory activity, and this could be rationalized by modeling based on the known fumagillin-MetAP2 crystal structure. The lead compound resulting from these studies, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (R)-1-amino-3-methyl-1-oxobutan-2-ylcarbamate, (PPI-2458), demonstrated an improved pharmacokinetic profile relative to the earlier clinical candidate TNP-470, and has advanced into phase I clinical studies in non-Hodgkins lymphoma and solid cancers.

Design, synthesis, and three-dimensional structural characterization of a constrained Ω-loop excised from interleukin-1α

Abstract The cyclic peptide 1 , containing a 2,7-disubstituted naphthalene spacer, was designed to mimic an exposed Ω-loop present in interleukin-1α, an important mediator of immune and inflammatory responses. The synthesis of this cyclic peptide was accomplished via solution phase fragment condensation methodology. The three dimensional characterization using 2D-NMR techniques revealed it to be an excellent mimic for the Ω-loop sequence 41–48 in interleukin -1α.

The Three-Dimensional X-Ray Crystal Structure of HIV-1 Protease Complexed with a Hydroxyethylene Inhibitor

The aspartyl proteinase encoded within the genome of the type I human immunodeficiency virus (HIV-1 PR) is a valid and important target for the development of a therapeutic to treat HIV infections. Progress in this area has been rapid due to 1) the wealth of previous experience with other aspartyl proteinases and 2) the massive commitment by a large number of research groups worldwide. In this chapter we would like to discuss some of our efforts to develop a PR inhibitor by describing the structure of a complex between HIV-1 PR and a hydroxyethylene inhibitor. As a final note before continuing, we would like to acknowledge the significant contributions that Alex Wlodawer and his group have made to this field which have been important to the progress made not only by our group but by many others as well.