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

Chao Zhang, 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 WuMarika Nespi, Wayne Spevak, Paul Lin, Keith Nolop, Peter Hirth, Gregory H Tesch, Gideon Bollag

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48 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)5689 - 5694
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number14
DOIs
Publication statusPublished - 2013

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