RESUMO
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-Hodgkin's lymphoma and solid cancers.
Assuntos
Aminopeptidases/antagonistas & inibidores , Carbamatos/química , Carbamatos/farmacologia , Cicloexanos/química , Cicloexanos/farmacologia , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Aminoácidos/química , Animais , Bovinos , Processos de Crescimento Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Modelos Moleculares , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Relação Estrutura-AtividadeRESUMO
Fumagillin, an irreversible inhibitor of MetAP2, has been shown to potently inhibit growth of malaria parasites in vitro. Here, we demonstrate activity of fumagillin analogs with an improved pharmacokinetic profile against malaria parasites, trypanosomes, and amoebas. A subset of the compounds showed efficacy in a murine malaria model. The observed SAR forms a basis for further optimization of fumagillin based inhibitors against parasitic targets by inhibition of MetAP2.
Assuntos
Aminopeptidases/antagonistas & inibidores , Antimaláricos/química , Cicloexanos/química , Ácidos Graxos Insaturados/química , Metaloendopeptidases/antagonistas & inibidores , Administração Oral , Aminopeptidases/metabolismo , Animais , Antimaláricos/síntese química , Antimaláricos/farmacologia , Cicloexanos/síntese química , Cicloexanos/farmacologia , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/farmacologia , Metaloendopeptidases/metabolismo , Camundongos , Testes de Sensibilidade Parasitária , Sesquiterpenos/síntese química , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.