A new compound NVP-BGJ398 improves the FGFR3 mutation related dwarfism in mice

Achondroplasia is caused by a gain-of-function mutation in FGFR3 that disrupts proliferation and differentiation in the bone growth plate, reducing growth severely.

As a potential therapy, a research team led by Laurence Legeai-Mallet, from INSERM-France, studied a compound: NVP-BGJ398, that is a tyrosine kinase inhibitor and targets members of the FGF receptor family, including FGFR3 in a mouse model of achondroplasia. (In JCI– Journal of clinical investigation)

Starting by the beginning: what is a cell?

The word cell means “small room” (from Latin cella) and is the basic structural, functional and biological unit of all known living organisms. Cells are often called the “building blocks of life”.

Most cells surface have microscopic entrances, like gates, that are called receptors. When activated, receptors stimulate intracellular specific particules/enzymes. In most cases, a chain of reactions transmits signals from the cell surface to a variety of intracellular targets and this is called signal transduction. Intracellular signaling pathways thus connect the cell surface to the nucleus, leading to changes in gene expression in response to extracellular stimuli.

A domino cascade can be a simple example of how a signals cascade occur inside the cell.

Image credits: wikipedia

In achondroplasia, FGFR3 has a mutation/alteration and exhibit exaggerated negative signalling.

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases, including FGFR3. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades.

In this new study, NVP-BGJ398 inhibited FGFR3 activity and rescued ex vivo growth of embryonic femurs from mice with dwarfims. The research team subsequently tested treatment of newborn mice for 15 days with NVP-BGJ398 and found that mice developed longer limbs relative to untreated controls.

Moreover, NVP-BGJ398 increased chondrocyte proliferation in growth-plate cartilage of the femurs and tibia. Treatment also rescued intervertebral disc and vertebrae anomalies and increased the length of the lumbar length. The authors compared postnatal treatment with NVP-BGJ398 to treatment with BMN111, a C-natriuretic peptide analog that is currently in a phase 2 trial for achondroplasia in their preclinical mouse model. These studies suggest that directly targeting hyperactive FGFR3 signaling may provide an early treatment option for achondroplasia.

The main question on this new compound is that it is a pan tyrosine kinase inhibitor (TKI), meaning this that affects all the FGFR´s: FGFR1, FGFR2 and FGFR4, what can be a totally unwanted characteristic. The goal is to inhibit only FGFR3.