2. Academic Validation
  3. Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site

Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site

  • Chemistry. 2017 May 2;23(25):6083-6093. doi: 10.1002/chem.201603222.
Sandip Murarka 1,  Pablo Martín-Gago 1,  Carsten Schultz-Fademrecht 2,  Alaa Al Saabi 2,  Matthias Baumann 2,  Eyad K Fansa 3,  Shehab Ismail 4,  Peter Nussbaumer 2,  Alfred Wittinghofer 3,  Herbert Waldmann 1 5
Affiliations

Affiliations

  • 1 Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.
  • 2 Lead Discovery Center GmbH, 44227, Dortmund, Germany.
  • 3 Max-Planck-Institut für Molekulare Physiologie, Structural Biology Group, 44227, Dortmund, Germany.
  • 4 Beatson Institute for Cancer Research, Bearsden, Glasgow, G61 1BD, UK.
  • 5 Technische Universität Dortmund, Fakultät Chemie, Chemische Biologie, Otto-Hahn-Straße 6, 44221, Dortmund, Germany.
PMID: 27809361 DOI: 10.1002/chem.201603222
Abstract

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.

Keywords

PDEδ; k-ras; small molecules; structure-based design; structure-property relationships.

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