RESUMEN
Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.
Asunto(s)
Reparación del ADN por Unión de Extremidades , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Ligandos , ADN/metabolismo , ADN Polimerasa thetaRESUMEN
As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas Lim/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , Factores Despolimerizantes de la Actina/metabolismo , Animales , Biotransformación , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Microsomas Hepáticos/metabolismo , Invasividad Neoplásica , Relación Estructura-ActividadRESUMEN
The Pd-catalyzed amination of a variety of heteroaryl halides has been accomplished by utilizing bulky electron-rich biaryl phosphine ligands. In particular, we report the first couplings of amines with chloro- and bromoindoles bearing a free NH, as well as the first Pd-catalyzed aminations of a 5-halopyrimidine. [reaction: see text]