Cell-based screen identifies porphyrins as FGFR3 activity inhibitors with therapeutic potential for achondroplasia and cancer

Sep 28, 2026

Overactive FGFR3 signaling contributes to cancers and short-limbed skeletal dysplasias, especially achondroplasia. The study builds a receptor/adaptor translocation assay to monitor FGFR3 activation and screen complex plant mixtures, identifying Amaranthus viridis extract activity. Two porphyrins, pheophorbidea and pyropheophorbide a, are isolated and characterized; pyropheophorbide a reduces excessive FGFR3 signaling by shortening FGFR3 half-life in FGFR3-overactivated multiple myeloma cells and chondrocytes. In humanized ACH mice, it improves long-bone growth defects, supporting a platform for FGFR3-targeted therapeutics.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

FGFR3 signaling in bone dysplasia and cancer

Current FGFR3-targeting strategies and limitations

Results

Cell-based monitoring system for early FGFR3 activation

Identification of porphyrin modulators from plant extracts

Effects on FGFR3 signaling, proliferation, apoptosis, and growth in models

RESE AR CH ARTICLE Conflict of interest: YCL, YTC, JYW, and HJK are inventors on a related pending patent application (PCT/ US2018/017376, US 2019/0361004 A1) assigned to Academia Sinica. Copyright: © 2023, Lin et al. This isan open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: April 6, 2023 Accepted: October 10, 2023 Published: October 12, 2023 Reference information: JCI Insight. 2023;8(22):e171257. [https://doi.org/10.1172/jci](https://doi.org/10.1172/jci). insight.171257. Cell-based screen identifies porphyrins as FGFR3 activity inhibitors with therapeutic potential for achondroplasia and cancer Yun-Wen Lin,1,2 Hsiao-Jung Kao,3 Wei-Ting Chen,1 Cheng-Fu Kao,1 Jer-Yuarn Wu,3 Yuan-Tsong Chen,3,4 and Yi-Ching Lee1,2 1Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan. 2Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. 3Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. 4Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA. Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, includingthe most common form of human dwarfism, achondroplasia (ACH). Targeting FGFR3 activity holds great promise as a therapeutic approach for treatment of these diseases. Here, we established a receptor/adaptor translocation assay system that can specifically monitor FGFR3 activation, and we applied it to identify FGFR3 modulators from complex natural mixtures. An FGFR3-suppressing plant extract of Amaranthus viridis was identified from the screen, and 2 bioactive porphyrins, pheophorbidea (Pa) and pyropheophorbide a, were sequentially isolated from the extract and functionally characterized. Further analysis showed that Pa reduced excessive FGFR3 signaling by decreasing its half-life in FGFR3-overactivated multiple myeloma cells and chondrocytes. In an ex vivo culture system, Pa alleviated defective long bone growth in humanized ACH mice (FGFR3ACH mice). Overall, our study presents an approach to discovery and validation of plant extracts or drug candidates that target FGFR3 activation. The compounds identified by this approach may have applications as therapeutics for FGFR3-associated cancers and skeletal dysplasias. Introduction Fibroblast growth factor receptor 3 (FGFR3) plays an important role in regulating linear bone growth (1) . Gain-of-function FGFR3 mutations have been shown to prolong FGFR3 signaling and disrupt proper chondrocyte proliferation and differentiation, leading to a group of skeletal dysplasias of varying severity (2) . Among these dysplasias, achondroplasia (ACH) is the most common form of human short-limbed dwarfism, affecting more than a quarter million people worldwide. More than 99% of individuals affected with ACH possess the same FGFR3G380R mutation (3–5) . Meanwhile, another FGFR3-associated dysplasia, thanatophoric dysplasia type I (TDI), is more severe than ACH and is typically fatal during the perinatal period. In addition to dysplasias, abnormal FGFR3 activation is frequently found in various types of somatic cancers, and it is associated with poor prognosis or higher risk of recurrence in multiple myeloma (MM) (6), bladder carcinoma, and cervical cancer (7) . Thus, FGFR3 activity is a promising therapeutic target for the treatment of various FGFR3-overactivated diseases. Several potential therapeutic strategies have been taken to develop treatments for FGFR3 skeletal dysplasias. These include targeting the FGF ligand, FGFR3, tyrosine kinase activity of FGFR3, or FGFR3 downstream signals (8–11) . Such efforts have led to the August 2021 US FDA approval of the first treatment for patients with ACH, a C-type natriuretic peptide analog called vosoritide (Voxzogo), which partially inhibits FGFR3 downstream signa

FAQs

What biological problem does the study address?

The study targets overactive FGFR3 signaling that drives cancers and skeletal dysplasias, particularly achondroplasia.

How did the researchers identify FGFR3 modulators?

They developed a cell-based receptor/adaptor translocation assay to monitor FGFR3 activation and used it to screen complex plant extracts for modulators.

Which compounds were found to inhibit FGFR3 activity, and what is their key mechanism?

Two bioactive porphyrins, pheophorbidea (Pa) and pyropheophorbide a, were isolated; pyropheophorbide a suppresses excessive FGFR3 signaling by decreasing FGFR3 half-life.

Sep 28, 2026

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