Beyond Achondroplasia

Growing together with Clara

New inhibitor of FGFR3 in mouse model


A therapeutic strategy to rescue dwarfism caused by FGFR3 gain-of-function mutations is to reduce or counteract the hyperactivity of FGFR3.

Many cancers have FGFR3 mutations, in which the FGFR3 has hyperactivity, 
which contrast to the hyperactivity of FGFR3 in achondroplasia, that 
reduces growth. FGFR3 mutation in cancer increase cell multiplication 
and growth.

A group of compounds tested and used with success to reduce some cancer growth are the TKIs (tyrosine kinase inhibitors), although TKIs have not been applied in skeletal disorders so far.

In 2011, a research team from Novartis (Vito Guagnano was the principal researcher) worked on series of existent compounds (ureas group) and modified them to create potent and selective inhibitors of FGFR1, FGFR2 and FGFR3 (fibroblast growth factor receptor tyrosine kinases 1, 2, and 3), the TKIs.

At that time, one of the compounds, named NVP-BGJ398 was selected for in vivo evaluation (tests in mice) and showed significant antitumor effect in the form of a bladder cancer xenograft models.  At that time, the research team concluded that the results supported the potential therapeutic use of NVP-BGJ38 as a new anticancer agent.


BGJ398 chemical structure. Credits: Selleckchem

in vivo evaluation - test/experiment done in a living organism, as a mouse

xenograft models - A surgical graft/piece of tissue from one species to an 
unlike species. The prefix "xeno-" means foreign.

In January 2016, a study by Dr. Gudernova, from the research team leaded by Prof. Krejci (ReACH registry – Czech Republic), tested the activity of 5 FGFR tyrosine kinase inhibitors (TKI´s) against FGFR signaling in chondrocytes:

  • SU5402
  • PD173074
  • AZD1480
  • AZD4547
  • BGJ398

This last compound, was the same NVP-BGJ398. Although all these five TKIs strongly inhibited FGFR activation in cultured chondrocytes and completely relieving FGFR inhibition of chondrocyte proliferation. When applied to to newborn mice, however, (a living organism and not just cells in culture dishes) TKIs did not improve skeletal growth and had lethal toxic effects on the liver, lungs and kidneys. So in a living organism the results were quite different and had negative side effects.

Cultured chondrocytes - cartilage cells that are put to grow under 
controlled conditions, outside the human body, in a laboratory.

Credits: Genengnews

Credits: Genengnews

Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over time, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity is yet to be evaluated.

Achondroplasia FACTS

1. Bone elongation relies on an active process controlled by proliferation and differentiation of chondrocytes within the growth plate.

2. the size of the the foramen magnum is much smaller in ACH patients, causing cervicomedullary compression. These data indicate there is an impact of FGFR3 on both mesenchymal (on the synchondroses) and neural crest–derived osteoblasts (on the nasal bone) and suggest an important role of FGFR3 on both intramembranous and endochondral ossification processes.

Recently, on the 2nd May 2016, Prof. Laurence Legeai-Mallet et al. published Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model

et al. - comes from Latin, et alia, and means "and others".

Highlights of this paper:

  1. NVP-BGJ398 inhibits FGFR3 phosphorylation (does not allow FGFR3 to perform its activities).
  1. NVP-BGJ398 was identified as a panspecific FGFR inhibitor  that was equally active against FGFR1, FGFR2, and FGFR3 and less active against FGFR4 (pan means “all”).
  1. Recently, cell-free kinase assays showed that NVP-BGJ398 was more selective for FGFR3 than the other FGFRs


  1. In this study, NVP-BGJ398 inhibited the hyperactivity of FGFR3
  1. NVP-BGJ398 rescued the anomalies of fetal calvaria (head bones) and femur in organ cultures of tissue taken from the Fgfr3Y367C/+ mouse model of ACH.
Fgfr3Y367C/+ mouse - mice that were developed in the lab to be born with thanatophoric
                     dysplasia, a much more serious, lethal bone dysplasia.
  1. The reduction in the activity of FGFR3 improved all pathological hallmarks of ACH in long bones, skull base, calvaria, intervertebral disc (IVD), and vertebrae.
STAT pathway downregulation - chondrocyte proliferation was restored

SOX9 and MAPK downregulation – chondrocyte differentiation was improved 

7. Induced femoral elongation by NVP-BGJ398 was dose dependent, confirming the role of FGFR3 as a negative regulator of bone growth

8. There were treated Fgfr3Y367C/+ newborn mice (P1) daily with subcutaneous injections of NVP-BGJ398             (2 mg per kg body weight per day)

9. NVP-BGJ398 improves growth of the axial skeleton (head and trunk bones) in Fgfr3Y367C/+ mice.

10. Data suggest a possible improvement of the ACH spinal stenosis phenotype with treatment.

11. NVP-BGJ398 improves the growth of the craniofacial skeleton in Fgfr3Y367C/+ mice.

12. NVP-BGJ398 treatment partially prevented the loss of 4 synchondroses (bone fusion, with no cartilage)

Synchondroses – sites of endochondral skull growth, located at the base of the skull. They are a form of cartilaginous joint.

13. The gain of growth of femurs and tibias was 50% higher in animals treated earlier and longer with NVP-BGJ398 from day 1 than those treated from day 7.


TOP conclusions

A) NVP-BGJ398 treatment also appeared more effective than BMN111 treatment, suggesting that directly targeting FGFR3 with a TKI may be a better approach than targeting FGFR3 downstream signaling pathways.

B) NVP-BGJ398 treatment for 10 days improved the bone growth 2 to 3 times more than what had been reported for BMN111.


14. NVP-BGJ398–mediated effects were mainly due to FGFR3 inhibition, with no other gross side effects being observed.

15. NVP-BGJ398, when applied from birth onwards, increased the size of the reduced FM and inhibited the premature fusion of synchondroses.

16. Treatment-related effects on the skull suggested the potential of correcting facial appearance in ACH patients and, most importantly, the potential of reducing the risks related to the cervicomedullary compression and early death that can occur in ACH children.

17. There is potential that longer NVPBGJ398 treatments could lead to a secondary positive effect on the resulting bone structure.


STUDY Protocols

2 protocols (P) applied to treat FGFR3 Y367C/+ mice

P 1: starts day 115 days long

P2:  start day 7 – 10 days long (similar to the one used for BMN111)



We have two recent studies on NVP-BGJ398, one mentioning the toxicity of this compound in in vivo experiments and the other with relevant data showing that this can be a possible therapy for achondroplasia. Much more needs to be investigated on this.

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