Important Compound Classes
Title
Bifunctional Substituted Pyrimidines as Modulators of FAK Proteolyse.
Patent Application Number
WO 2020/023851 A1
Publication Date
January 30, 2020
Priority Application
US 62/703,800
Priority Date
July 26, 2018
Inventors
Crews, C. M.; Cromm, P. M.; Crew, A. P.
Assignee Company
Yale University, Office of Cooperative Research, Two Whitney Avenue, New Haven, Connecticut 06510 (US). Arvinas Operations, INC., Five Science Park, New Haven, Connecticut 06511 (US).
Disease Area
Cancer
Biological Target
Focal adhesion kinase (FAK) or protein tyrosine kinase 2 (PTK2).
Summary
Protein degradation induced by small-molecules is emerging as an orthogonal therapeutic strategy that has the potential to expand the druggable target space, especially for targets that were once thought to be undruggable. Previous efforts to modulate focal adhesion kinase (FAK) activity were limited to kinase inhibitors, which resulted with low success in clinical studies. The overexpression and activation of FAK is associated with several human malignant diseases, including esophageal, ovarian, colorectal, and hepatocellular carcinoma (HCC). HCC is the most common type of liver cancer in humans, accounting for 70–85% of primary liver malignancies, resulting in the third leading cause of cancer-related deaths worldwide.
Protein degradation now offers a possibility to simultaneously block FAK’s kinase signaling and scaffolding capabilities. FAK is an essential cytoplasmic tyrosine kinase that controls many aspects in tumor invasion and metastasis and simultaneously acts as a kinase and a scaffold for several signaling proteins. The FAK scaffolding domains at the plasma membrane are primarily involved in the formation of large signaling complexes. When FAK is activated, it triggers the engagement of membrane proteins such as integrins, resulting in FAK four-point-one, ezrin, radixin, moesin (FERM) domain displacement and subsequent autophosphorylation. FAK contains four linearly arranged functional domains from its N terminus: the FERM domain, the catalytic kinase domain, three proline-rich regions, and the focal adhesion targeting domain. The FAK FERM domain contains a nuclear localization sequence that regulates cellular function by binding to membrane proteins (growth factor receptors and chemokine receptors) and nuclear proteins. FAK kinase domain contains the activation loop and tyrosine sites, which ultimately regulate FAK kinase activity.
The present FAK kinase inhibitors cannot be investigated or blocked with reported kinase inhibitor as conventional kinase inhibitors can only act on the protein kinase domain, which may lead to drug resistance. The overall poor patient survival is associated with increased FAK expression and activity found in primary and metastatic cancers of many tissues. Consequently, FAK has become an interesting target for drug discovery, and as a consequence populates multiple compounds in clinical trials. Furthermore, FAK activity has been associated with the glycoprotein killer T cell (CD8+ T cell) dysfunction and is now believed to be a valuable target for cancer immunotherapy. A practical strategy against both kinase dependent enzymatic functions and kinase-independent scaffolding functions of FAK is an urgent and meaningful need for FAK-related diseases.
The present Patent Highlight identifies the suitable linker length for a FAK-PROTAC library. The position of the linker connecting to the binders and the rigidity of the linker were important in modulating the interaction of the target protein and E3 ligase, which directly determine degradation efficacy. Proteolysis targeting chimera (PROTAC) are heterobifunctional small molecules containing two recognition moieties and represent a novel chemical knockdown technology for the post-translational proteins of interest. PROTAC specifically bind an E3 ubiquitin ligase, and the other specifically binds the target protein, which eventually drive E3 ubiquitin ligase to the target protein, resulting in ubiquitination of the target protein and consequent proteasome-mediated degradation. The von Hippel–Lindau (VHL) protein complex and the cereblon (CRBN) complex are the most common E3 ligases currently recruited using PROTAC that can exhibit different degradation selectivity and efficacy. The present PROTAC consist of an E3 ubiquitin ligase binding moiety (ULM) and a protein/polypeptide targeting moiety (PTM) that binds a target protein such that the target protein/polypeptide is placed in close proximity to the ubiquitin ligase to effect degradation of that protein. The ULM can be VHL, CRBN, a mouse double minute 2 homologue (MDM2), or an IAP E3 ubiquitin ligase binding moiety. In addition, L is a linker that is a bond or a chemical group that couples PTM to ULM.
Key Structures
Biological Assay
The PC3 and MDA-MB-231 cell lines were used for immunoblotting and the assays that inform cell proliferation, kinase activity, wound healing, and Transwell invasion.
Biological Data
The table below shows exemplary compounds that demonstrated FAK target
protein degradation. The FAK-degrading compounds were designed based
on one of the most advanced FAK inhibitors defactinib. PK-data showed
that the IV and IP routes of administration were effective at increasing
plasma levels of compounds 100, 101, 102, 103, and 107.
Recent Review Articles
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The author declares no competing financial interest.