TYRA-300, an FGFR3 selective inhibitor, promotes bone growth in two FGFR3-driven models of chondrodysplasia

Jacqueline H. Starrett; Clara Lemoine; Matthias Guillo; Chantal Fayad; Nabil Kaci; Melissa Neal; Emily Pettitt; Melissandre Pache; Qing Ye; My Chouinard; Eric L. Allen; Geneviève Baujat; Robert L. Hudkins; Michael B. Bober; Todd Harris; Ronald V. Swanson; Laurence Legeai-Mallet

doi:10.1172/jci.insight.189307

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

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¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

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¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

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¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

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¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

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¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Neal, M. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

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¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Pache, M. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Ye, Q. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Chouinard, M. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Allen, E. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Baujat, G. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Hudkins, R. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Bober, M. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Harris, T. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Swanson, R. in: JCI | PubMed | Google Scholar

¹Tyra Biosciences, Carlsbad, United States of America

²Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplas, Université de Paris Cité, Imagine Institute, INSERM U1163, Paris, France

Find articles by Legeai-Mallet, L. in: JCI | PubMed | Google Scholar

JCI Insight. https://doi.org/10.1172/jci.insight.189307.
Copyright © 2025, Starrett et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published April 3, 2025 - Version history

Achondroplasia (ACH) and hypochondroplasia (HCH), the two most common types of dwarfism, are each caused by FGFR3 gain-of-function mutations that result in increased FGFR3 signaling, disrupting chondrogenesis and osteogenesis resulting in disproportionately shortened long bones. In this study, TYRA-300, a potent and selective FGFR3 inhibitor, was evaluated in three genetic contexts: wild-type mice, the Fgfr3^Y367C/+ mouse model of ACH, and the Fgfr3^N534K/+ mouse model of HCH. In each model, TYRA-300 treatment increased naso-anal length, tibia and femur length. In the two FGFR3-altered models, TYRA-300-induced growth partially restored the disproportionality of long bones. Histologic analysis of the growth plate in Fgfr3^Y367C/+ mice revealed that TYRA-300 mechanistically increased both proliferation and differentiation of chondrocytes. Importantly, children with ACH can experience medical complications due to foramen magnum stenosis, and TYRA-300 significantly improved the size and shape of the skull and foramen magnum in Fgfr3^Y367C/+ mice. Spinal stenosis is also a frequent complication, and TYRA-300 increased the lumbar vertebrae length and improved the shape of the intervertebral discs in both models. Taken together, these studies demonstrate that the selective FGFR3 inhibitor TYRA-300 led to a significant increase in bone growth in two independent FGFR3-driven preclinical models as well as in wild-type mice.

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TYRA-300, an FGFR3 selective inhibitor, promotes bone growth in two FGFR3-driven models of chondrodysplasia

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TYRA-300, an FGFR3 selective inhibitor, promotes bone growth in two FGFR3-driven models of chondrodysplasia

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