Reducing FGFR3 influence in achondroplasia, part 2

Targeting FGFR3 inside the chondrocyte

Inhibiting fibroblast growth factor receptor 3 (FGFR3) activity in achondroplasia may restore, at least partially, the bone growth, which in turn may prevent the common orthopedic complications most of affected kids will suffer during the childhood and, in consequence, may also reduce the very well-known skeletal and neurological complications commonly seen in affected adults.

In the last post, we have made a short review of potential approaches aiming the inhibition of FGFR3 to reduce its activity in achondroplasia, outside the chondrocyte.  We will begin to dive into the chondrocyte, looking at where else we can beat the overactive FGFR3.

Transmembrane interceptors

The first stop we will make is inside the cell membrane, the cell cover sheet that protects the cell content and works like a gate. As you may remember, FGFR3 is positioned across the chondrocyte cell membrane. FGFR3 is constituted of three parts, called extracellular, transmembrane and intracellular domains. Let’s take a look in the transmembrane domain.

When FGFR3 is activated by a FGF, it attracts another receptor and the two FGFR3s form what is called a dimmer. The bodies of both receptors align in a way to allow the exposure of the phosphate binding sites (the ATP pockets mentioned in a previous article), which are like electric plugs. These electric plugs are those that will start the FGFR3 signaling cascade.

It is possible to develop compounds capable of hindering the dimmer alignment. These molecules have been called transmembrane interceptors. The concept is to use the propensity receptor enzymes (like FGFR3) have to attract one another to form the dimmer. It is possible to build an amino acid chain, a peptide, with the same (and attractive) composition of the transmembrane domain of the receptor. This peptide can then be used as competitor of the real receptor. If the activated receptor binds to such peptide, it cannot reach the right configuration to activate the electric plugs and will remain inactive. Conceptual experiments have already been performed with a FGFR3 model by the group of Dr. Kalina Hristova, one of the researchers who have been dedicating strong efforts to understand the FGFR3 and its biological characteristics. For more technical information, there is a nice short review published in Science Signaling.

Research with these ´interceptors´ is still in the beginning, but there are some positive aspects in this potential approach: it is likely a peptide directed to FGFR3 transmembrane domain would be very specific; it would not have to enter the cell and face cell clearance (janitor) mechanisms and perhaps it would have the correct size to reach the chondrocytes.

In the next post we will review the currently most prominent class of drugs designed to block receptor and intracellular enzymes, the tyrosine kinase inhibitors.