Abstract
Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.
Highlights
Cancer is recognized as a complex process involving tumor cell transformation, and the surrounding microenvironment
We report that altiratinib exhibits balanced inhibition in vitro and in vivo, and inhibits three major microenvironmentvascularization and drug resistance pathways (HGF, VEGF, ANG), allows for pronounced MET inhibition in tumors, and blocks tumor invasion and metastasis
The discovery of altiratinib was based on the rationale of incorporating balanced inhibition of MET, TIE2, and VEGFR2 kinases within a single therapeutic
Summary
Cancer is recognized as a complex process involving tumor cell transformation, and the surrounding microenvironment. Referred to as the hallmarks of cancer, this holistic approach to understanding cancer identifies cross-talk mechanisms between tumor cells and cells of the microenvironment as essential for tumor growth, invasion, and metastasis [1]. New targeted therapeutics that block multiple hallmark mechanisms of cancer are highly sought. We disclose altiratinib as such an agent that addresses multiple mechanisms of tumor and microenvironment-mediated tumor growth and progression. The HGF–MET axis is involved in the etiology and progression of many human cancers [2,3,4]. HGF (hepatocyte growth factor), the ligand for the MET receptor tyrosine kinase, is
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