Highly Selective Focal Adhesion Kinase (FAK) Inhibitors

Project Overview

• Focal adhesion kinase (FAK) is a tyrosine kinase with important roles in cellular adhesion, cellular migration, and apoptosis. Overexpression of FAK is observed in many cancers, including breast, ovarian, pancreatic, and colorectal cancers.

• Several non-selective FAK inhibitors based on cyclic or bicyclic core scaffolds have been advanced to clinical trials, but their off-target effects can lead to undesirable cellular toxicity or hinder the development of combination formulations by interacting negatively with other drugs.
• Dana-Farber researchers have discovered a tricyclic core that serves as an effective scaffold for the development of selective and potent kinase inhibitors, which is available through an exclusive license.

Technology

Targeted disruption of FAK is of interest, both for the development of oncology drugs and use in basic molecular biology research. Several FAK inhibitors based on cyclic or bicyclic core scaffolds have been advanced to clinical trials. These molecules are ATP-competitive inhibitors and display either dual kinase inhibition or significant activity against other kinases. However, off-target effects from non-selective inhibitors can lead to undesirable cellular toxicity or hinder the development of combination formulations by interacting negatively with other drugs. In addition, there is a need in chemical biology research for more selective inhibitors to serve as chemical probes in studies exploring the role of FAK in cancer progression. 

Researchers at Dana Farber Cancer Institute have discovered a tricyclic core that serves as an effective scaffold for the development of selective and potent kinase inhibitors. A detailed and systematic structure-activity relationship campaign identified substituents with extremely high selectivity for FAK.

Further modifications to the side chains yielded several candidates with high potency against FAK (IC₅₀ < 50 nM). Pharmacokinetic profiling in mice demonstrated that these compounds are metabolically stable and exhibit low clearance (18.5 mL/min/kg). Testing of these compounds in 3D breast and gastric cancer models resulted in pronounced anti-proliferative effects and reduced migration of malignant cells. 

Further Details:

Groendyke and Gray et al. “Discovery of a pyrimidothiazolodiazepinone as a potent and selective focal adhesion kinase (FAK) inhibitor.” ACS Medicinal Chemistry Letters (2021), 12. 30-38.

Team Members: Nathanael S. Gray, PhD, Brian Groendyke, PhD, Behnam Nabet, PhD

Applications

• Therapeutic for cancers in which FAK is overexpressed

• Research tool for investigating FAK interactions

• Possible candidate for the development of combination therapies

Opportunities

Dana-Farber is seeking an Exclusive License for this technology.