Myeloid cell leukemia-1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.

No abstract

Fragmentsuche: Liganden, die an die GTPase K‐Ras binden und die Aktivität des Nukleotidaustauschfaktors Sos verändern, wurden mit einem fragmentbasierten Screening unter Verwendung von NMR‐Spektroskopie gefunden. Strukturdaten zeigen, wie die von den Fragmenten abgeleiteten Treffer an den K‐Ras‐Guanosindiphosphat‐Komplex binden (siehe Bild), und liefern einen Ausgangspunkt für die Entwicklung von Wirkstoffen, die K‐Ras‐Aktivierung und ‐Signalisierung beeinflussen.

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100 fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.

In the last 20years, the availability of precision chemical tools (e.g. controlled/living polymerizations, 'click' reactions) has determined a step change in the complexity of both the macromolecular architecture and the chemical functionality of biodegradable polyesters. A major part in this evolution has been played by the possibilities that controlled macromolecular branching offers in terms of tailored physical/biological performance. This review paper aims to provide an updated overview of preparative techniques that derive hyperbranched, dendritic, comb, grafted polyesters through polycondensation or ring-opening polymerization mechanisms.