RESUMEN
Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Masculino , Neoplasias/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéuticoRESUMEN
In order to put the previously proposed concept of directed evolution of hybrid catalysts (proteins that harbor synthetic transition-metal catalysts or organocatalysts) into practice, several prerequisites must be met. The availability of a robust host protein that can be expressed in sufficiently large amounts, and that can be purified in a simple manner is crucial. The thermostable enzyme tHisF from Thermotoga maritima, which constitutes the synthase subunit of a bi-enzyme complex that is instrumental in the biosynthesis of histidine, fulfills these requirements. In the present study, fermentation has been miniaturized and parallelized, as has purification of the protein by simple heat treatment. Several mutants with strategically placed cysteines for subsequent bioconjugation have been produced. One of the tHisF mutants, Cys9Ala/Asp11Cys, was subjected to bioconjugation by the introduction of a variety of ligands for potential metal ligation, of a ligand/metal moiety, and of several organocatalytic entities that comprise a flavin or thiazolium salts. Characterization by mass spectrometry and tryptic digestion was achieved. As a result of this study, a platform for performing future directed evolution of these hybrid catalysts is now available.
Asunto(s)
Quelantes/química , Proteínas/química , Catálisis , Quelantes/síntesis química , Expresión Génica , Ligandos , Maleimidas/síntesis química , Maleimidas/química , Modelos Moleculares , Estructura Molecular , Mutación/genética , Unión Proteica , Proteínas/genética , Proteínas/aislamiento & purificación , Proteínas/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
New oligomers or polymers are prepared by polymerization of arsonium ylides in the presence of boron compounds.