Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site.
The K-Ras GTPase is a major target in anticancer drug discovery. However, direct interference with signaling by K-Ras has not led to clinically useful drugs yet. Correct localization and signaling by farnesylated K-Ras is regulated by the prenyl binding protein PDEδ. Interfering with binding of PDEδ to K-Ras by means of small molecules provides a novel opportunity to suppress oncogenic signaling. Here we describe the identification and structure-guided development of novel K-Ras-PDEδ inhibitor chemotypes based on pyrrolopyridazinones and pyrazolopyridazinones that bind to the farnesyl binding pocket of PDEδ with low nanomolar affinity. We delineate the structure-property relationship and in vivo pharmacokinetic (PK) and toxicokinetic (Tox) studies for pyrazolopyridazinone-based K-Ras-PDEδ inhibitors. These findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic Ras.
Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.
Sandip
S
Murarka
Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.
Pablo
P
Martín-Gago
Lead Discovery Center GmbH, 44227, Dortmund, Germany.
Carsten
C
Schultz-Fademrecht
Lead Discovery Center GmbH, 44227, Dortmund, Germany.
Alaa
A
Al Saabi
Lead Discovery Center GmbH, 44227, Dortmund, Germany.
Matthias
M
Baumann
Max-Planck-Institut für Molekulare Physiologie, Structural Biology Group, 44227, Dortmund, Germany.
Eyad K
EK
Fansa
Beatson Institute for Cancer Research, Bearsden, Glasgow, G61 1BD, UK.
Shehab
S
Ismail
Lead Discovery Center GmbH, 44227, Dortmund, Germany.
Peter
P
Nussbaumer
Max-Planck-Institut für Molekulare Physiologie, Structural Biology Group, 44227, Dortmund, Germany.
Alfred
A
Wittinghofer
Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.|Technische Universität Dortmund, Fakultät Chemie, Chemische Biologie, Otto-Hahn-Straße 6, 44221, Dortmund, Germany.
Herbert
H
Waldmann
PDEδ; k-ras; small molecules; structure-based design; structure-property relationships