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Highly Selective Focal Adhesion Kinase (FAK) Inhibitors

Dana-Farber

Small molecule

Oncology

Hit To Lead or Lead Optimization

Background

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. 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. 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. 

Technology Overview

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. 

Benefits

• High selectivity for FAK
• Potent inhibitor (IC50 < 50 nM)
• Displays anti-proliferative activity in 3D breast and gastric cancer models

Applications

• Therapeutic for cancers in which FAK is overexpressed
• Research tool for investigating FAK interactions
• Possible candidate for the development of combination therapies

 

Groendyke, B and Gray, N. S.

PCT-US2020-031791 (2020.05.07)
Patent Family: US, EP, CN, CA, AU

"Discovery of a pyrimidothiazolodiazepinone as a potent and selective focal adhesion kinase (FAK) inhibitor". Groendyke, B. J. et al. ACS Medicinal Chemistry Letters, (2020) 12(1), 30–38. https://doi.org/10.1021/acsmedchemlett.0c00338

DANA_Pub_Discovery of a pyrimidothiazolodiazepinone as a potent and selective focal adhesion kinase (FAK) inhibitor.pdf
DANA_Patent_WO 2020-231726 A1.pdf
DANA_Poster_Highly Selective Focal Adhesion Kinase (FAK) Inhibitors.pdf