The Development of FAK Inhibitors: A Five-Year Update

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia. This review is focused on compounds able to block FAK with different potencies and with different mechanisms of action, that have appeared in the literature since 2017. Furthermore, new emerging PROTAC molecules have appeared in the literature. This summary could improve knowledge of new FAK inhibitors and provide information for future investigations, in particular, from a medicinal chemistry point of view.

Keywords: FAK inhibitors; PROTAC; anticancer compounds; focal adhesion kinase; medicinal chemistry; pyrimidines; triazines.

Figure 1

Superposition of the FAK-TAE226 (PDB code: 2JKK) and FAK-PF573228 (PDB code: 6YOJ) complexes. The carbon atoms of the two ligands are colored green (PF573228) and purple (TAE226). Carbon atoms of the protein are displayed in black. Oxygen, nitrogen, chlorine and sulfur atoms are represented in red, blue, dark green and yellow, respectively. Relevant residues lining the binding site are displayed. The molecular surface of the binding is shown as a grey grid.

Figure 2

2,4-Diphenylpyrimidines (DPPY) as FAK inhibitors. The pyrimidine nucleus and labelled fluorine atom are reported in red and green, respectively.

Figure 3

Irreversible pyrimidines as FAK inhibitors. The pyrimidine nucleus is reported in red.

Figure 4

FAK-13 crystallographic complex (PDB code: 6GCX). The ligand carbon atoms are coloured cyan. Carbon atoms of the protein are displayed in black. Oxygen, nitrogen and sulfur atoms are represented in red, blue and yellow, respectively. The three hydrogen bonds stabilising the complex are represented as dotted red lines. The covalently modified Cys427 is represented in a stick model. Selected residues limiting the binding site are shown.

Figure 5

Chemical structure of triazine compounds as FAK inhibitors.

Figure 6

Structures of 7H-pyrrolo[2,3-d]pyrimidines and thieno[3,2-d]pyrimidines as FAK inhibitors.

Figure 7

Other miscellaneous compounds as FAK inhibitors.

Figure 8

PROTAC molecules as FAK inhibitors.

Figure 9

PROTAC- GSK215 in complex with FAK and pVHL:ElonginC:ElonginB (PDB code: 7PI4). The macromolecules forming the complex are differently colored as indicated. The carbon atoms of PROTAC ligand are reported in cyan. A zoom view of the ligand binding site is reported in the panel. FAK residues are colored grey, whereas VHL residues are shown in green. Oxygen, nitrogen, fluorine and sulfur atoms are represented in red, blue, light green and yellow, respectively. The hydrogen bonds between the ligand and the proteins are indicated as dotted red lines. Relevant water molecules are reported as red dots.