2. Academic Validation
  3. Inhibitors to Overcome Secondary Mutations in the Stem Cell Factor Receptor KIT

Inhibitors to Overcome Secondary Mutations in the Stem Cell Factor Receptor KIT

  • J Med Chem. 2017 Nov 9;60(21):8801-8815. doi: 10.1021/acs.jmedchem.7b00841.
Helena Kaitsiotou 1,  Marina Keul 1,  Julia Hardick 1,  Thomas Mühlenberg 2 3,  Julia Ketzer 2 3,  Christiane Ehrt 1,  Jasmin Krüll 1,  Federico Medda 4,  Oliver Koch 1,  Fabrizio Giordanetto 4,  Sebastian Bauer 2 3,  Daniel Rauh 1
Affiliations

Affiliations

  • 1 Faculty of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 4a, D-44227 Dortmund, Germany.
  • 2 Department of Medical Oncology, Sarcoma Centre West German Cancer Centre University Duisburg-Essen, Medical School , Hufelandstraße 55, D-45122 Essen, Germany.
  • 3 Germany and German Cancer Consortium (DKTK), Partner Site University Hospital Essen , D-45147 Essen, Germany.
  • 4 Taros Chemicals GmbH & Co. KG , Emil-Figge-Straße 76a, D-44227 Dortmund, Germany.
PMID: 28991465 DOI: 10.1021/acs.jmedchem.7b00841
Abstract

In modern Cancer therapy, the use of small organic molecules against Receptor Tyrosine Kinases (RTKs) has been shown to be a valuable strategy. The association of Cancer cells with dysregulated signaling pathways linked to RTKs represents a key element in targeted Cancer therapies. The tyrosine kinase mast/stem cell growth factor receptor KIT is an example of a clinically relevant RTK. KIT is targeted for Cancer therapy in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). However, acquired resistance mutations within the catalytic domain decrease the efficacy of this strategy and are the most common cause of failed therapy. Here, we present the structure-based design and synthesis of novel type II kinase inhibitors to overcome these mutations in KIT. Biochemical and cellular studies revealed promising molecules for the inhibition of mutated KIT.

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