Metall‐Bis(2‐picolyl)amin‐Komplexe als Zustand‐1(T)‐Inhibitoren für aktiviertes Ras‐Protein

Abstract

Allosterische Stabilisierung: Metall(II)‐Cyclene sind Inhibitoren für die Ras‐ Effektor‐Wechselwirkung, da sie einen schwach Effektor‐bindenden Konformationszustand (Zustand 1(T) in Ras) stabilisieren, und binden direkt im aktiven Zentrum. Der neue Zustand‐1(T)‐Inhibitor Zn2+‐BPA (BPA=Bis(2‐picolyl)amin) bindet außerhalb der Nukleotid‐Bindetasche, stabilisiert aber trotzdem den Zustand 1(T) und kann so die Ras‐Raf‐Wechselwirkung unterbinden.

Distinct Conformational States of the Alzheimer β‐Amyloid Peptide Can Be Detected by High‐Pressure NMR Spectroscopy

“…Stabilization of the partially folded state 2' (inhibiting the formation of state 1) by small molecules could also be a suitable mechanism for drug development by weakening the monomer-oligomer interaction similar to the mechanism successfully demonstrated for the interaction of effectors with oncogenic Ras. [28,29] …”

The small GTPases Ras and Rheb studied by multidimensional NMR spectroscopy: structure and function

“…The synthesised compounds rely on the mutant cysteine to be present in the GTPase amino acid sequence for binding due to acrylamide and sulphonamide coupling groups and should therefore not affect the wild-type protein. This binding pocket for these compounds differs from the site previously described and is located between the central β-sheet of Ras, and the α2-(switch II), and α3-helices (Maurer et al, 2012;Rosnizeck et al, 2012;Sun et al, 2012;Ostrem et al, 2013;Schoepel et al, 2013). Like the aforementioned other binding pockets, this ligand binding cavity does not exist in the crystal structures of GDP-bound wildtype Ras and hence is probably highly dynamic in solution.…”

“…Moreover, on the basis of these measurements only, the Ras protein was believed to be undruggable, since it lacks hydrophobic cavities on its molecular surface (Cox et al, 2014). Nevertheless, during the past years several small molecules and zinc-chelating compounds have been identified and characterised as Sos antagonists of K-Ras (Palmioli et al, 2009;Rosnizeck et al, 2012). In 2012, co-crystal structures of several ligands bound to the fulllength and truncated Ras were published (Maurer et al, 2012;Sun et al, 2012).…”

“…Although several (fragment-based) screenings for small molecular antagonists of protein-protein interactions between Ras and its effectors have been proven to be difficult as affinities remain often rather low (Ganguly et al, 1998;Maurer et al, 2012;Rosnizeck et al, 2012;Cox et al, 2014;Schoepel et al, 2016), GTP analogues that bind tightly or even irreversibly to Ras could in principle lead to severe side effects because of unselective crossreactivities towards other GTPases. Nonetheless, a promising study recently reported on selectively targeting a Cys mutant of Ras (Ostrem et al, 2013;Hunter et al, 2014;Min Lim et al, 2014;Wiegandt et al, 2015;Ostrem and Shokat, 2016).…”

Intrinsische allosterische Hemmung von Signalproteinen durch Stabilisierung gering besetzter, durch Hochdruck‐NMR‐Spektroskopie nachweisbarer Interaktionszustände

“…Die Anpassung einer Taylor-Reihe zweiter Ordnung [Gl. [12][13][14][15] Qualitativ kçnnen hohe Druckkoeffizienten mit großen Strukturänderungen in der Nähe des betrachteten Atoms assoziiert werden, obwohl fehlende Verschiebungsänderungen nicht notwendigerweise die Abwesenheit von Strukturänderungen bedeuten. Die 1 H-und 15 N-NMR-chemischen Verschiebungen wurden für druckinduzierte Random-Coil-Effekte [11] korrigiert und zeigen daher nur strukturspezifische Druckeffekte (Abbildungen S2 und S3).…”