2. Academic Validation
  3. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor

Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor

  • Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5689-94. doi: 10.1073/pnas.1219457110.
Chao Zhang 1,  Prabha N Ibrahim,  Jiazhong Zhang,  Elizabeth A Burton,  Gaston Habets,  Ying Zhang,  Ben Powell,  Brian L West,  Bernice Matusow,  Garson Tsang,  Rafe Shellooe,  Heidi Carias,  Hoa Nguyen,  Adhirai Marimuthu,  Kam Y J Zhang,  Angela Oh,  Ryan Bremer,  Clarence R Hurt,  Dean R Artis,  Guoxian Wu,  Marika Nespi,  Wayne Spevak,  Paul Lin,  Keith Nolop,  Peter Hirth,  Greg H Tesch,  Gideon Bollag
Affiliations

Affiliation

  • 1 Plexxikon Inc., Berkeley, CA 94710, USA. CZhang@plexxikon.com
PMID: 23493555 DOI: 10.1073/pnas.1219457110
Abstract

Inflammation and Cancer, two therapeutic areas historically addressed by separate drug discovery efforts, are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and Cancer cells. Agents that target specific compartments of the immune system, therefore, not only bring new disease modifying modalities to inflammatory diseases, but also offer a new avenue to Cancer therapy by disrupting immune components of the microenvironment that foster tumor growth, progression, immune evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) are two hematopoietic cell surface receptors that regulate the development and function of macrophages and mast cells, respectively. We disclose a highly specific dual FMS and KIT kinase inhibitor developed from a multifaceted chemical scaffold. As expected, this inhibitor blocks the activation of macrophages, osteoclasts, and mast cells controlled by these two receptors. More importantly, the dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and Cancer.

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