Discovery of dual Axl/VEGF-R2 inhibitors as potential anti-angiogenic and anti-metastatic drugs for cancer chemotherapy

Dane Goff; Jing Zhang; Thilo Heckrodt; Jiaxin Yu; Pingyu Ding; Raj Singh; Sacha Holland; Weiqun Li; Mark Irving

doi:10.1016/j.bmcl.2017.06.071

Discovery of dual Axl/VEGF-R2 inhibitors as potential anti-angiogenic and anti-metastatic drugs for cancer chemotherapy

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3766-3771. doi: 10.1016/j.bmcl.2017.06.071. Epub 2017 Jun 28.

Authors

Dane Goff¹, Jing Zhang², Thilo Heckrodt², Jiaxin Yu², Pingyu Ding², Raj Singh², Sacha Holland², Weiqun Li², Mark Irving²

Affiliations

¹ Rigel Pharmaceuticals, 1180 Veterans Blvd., South San Francisco, CA 94080, USA. Electronic address: dagoff@att.net.
² Rigel Pharmaceuticals, 1180 Veterans Blvd., South San Francisco, CA 94080, USA.

PMID: 28711351
DOI: 10.1016/j.bmcl.2017.06.071

Abstract

Axl tyrosine kinase has been shown to be involved in multiple pathways contributing to tumor development, angiogenesis, and metastasis. High Axl expression has been observed in many human tumors where it appears to confer aggressive tumor behavior. Here we present several series of dual Axl-VEGF-R2 kinase inhibitors based on extensive optimization of an acyl diaminotriazole. It was hypothesized that dual inhibition of these two receptor tyrosine kinases may have a synergistic affect in inhibiting tumor angiogenesis and metastasis. One of these molecules, R916562 showed comparable activity to Sunitinib in two mouse tumor xenograft models and a mouse corneal micropocket model.

Keywords: Axl tyrosine kinase inhibitor; Diaminotriazole; VEGF-R2.

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Axl Receptor Tyrosine Kinase
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Mice
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Rats
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor Receptor-2
Axl Receptor Tyrosine Kinase