Achondroplasia: Therapeutical approach with irreversible FGFR3-tyrosine kinase inhibitor – ATAK

Fibroblast Growth Factor Receptor 3 (FGFR3) belongs to a family of structurally tyrosine kinase related receptors. Various mutations in FGFR3 have been shown to result in the most frequent dwarfisms, hypochondroplasia (HCH) and achondroplasia (ACH) (1/ 10 000). FGFR3 mutations lead to the constitutive activation of the receptor, producing the disruption of endochondral ossification, chondrocyte proliferation and maturation; and affect many signaling pathways.
At present, no specific treatment for these chondrodysplasia’s family is available. In this proposal, we will develop a novel therapeutic approach for ACH and HCH. For this purpose, we will generate irreversible inhibitors targeting selectively FGFR3 in the allosteric site of the tyrosine kinase domain. These tyrosine kinase inhibitors (TKI) will be able to reduce or stop the excessive Fgfr3 phosphorylation and thus restore bone growth.
The originality and strength of this project is the close collaboration between three partners with various and complementary domains of competence. Indeed, partner 2 has developed two distinct families of FGFR3 inhibitors with IC50 in the micromolar range. Partner 3 has obtained a first model of FGFR3 kinase domain and demonstrated that the compounds of partner 2 could be transformed in irreversible inhibitors. Partner 1 has demonstrated, for the first time that TKI can stop in vitro the constitutive phosphorylation of FGFR3 and correct ex vivo the bone growth of femurs from Fgfr3Y367C/+ mice.
In this context, we propose to synthetize novel TKI more specific to FGFR3. To do this, we will transform our TKI into irreversible ones (partner 2). This step will be facilitated by a computational approach (partner 3). We will undertake computational studies to guide the chemical synthesis in the rational conception of such inhibitors that need to be properly customized. The validation of these irreversible TKI will be done by partner 1 through cellular studies made with FGFR3 mutant constructs and human chondrocytes lines.
The best irreversible TKI will be analyzed ex-vivo to test their impact on the fetal growing skeleton of Fgfr3Y367C/+ mice. The cellular proliferation and differentiation in the growth plate in treated or untreated ex-vivo femurs will be analyzed. Finally, the best irreversible TKI will be evaluated in vivo in Fgfr3Y367C/+mice following multiple subcutaneous administrations of TKI. We expect a significant correction of the size and architecture of the growth plate. These preclinical data are required for the patenting process and are conducted to gather evidence justifying clinical trials for patients.
In conclusion, this strategy is the most relevant one in the field of tyrosine kinase inhibitors and therefore it should lead to the first selective FGFR3-inhibitors. These irreversible FGFR3 inhibitors should present improved pharmacological properties and thus will offer new perspective of treatment for achondroplasia and hypochondroplasia.