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Development of a degrader against oncogenic fusion protein FGFR3-TACC3
Norihito Shibata1, Nobuo Cho2, Hiroo Koyama2
1Division of Biochemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan.
Abstract:
Fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3), which has been identified in many cancers such as glioblastoma and bladder cancer, is a potent oncogenic fusion protein that induces constitutive activation of FGFR signaling, resulting in uncontrolled cell proliferation. Although several tyrosine kinase inhibitors against FGFR are currently under development, resistance to such types of inhibitors in patients has become a concern. In this study, a chimeric molecule SNIPER(TACC3)-11 (5a) was developed and found to reduce FGFR3-TACC3 levels effectively. Compound 5a conjugated KHS108 (a TACC3 ligand) to an LCL161 derivative (11) (an inhibitor of apoptosis protein [IAP] ligand) with a PEG linker (n = 2). Mechanistical analysis showed that cellular IAP1 was required for the reduction of FGFR3-TACC3 levels. Consistent with the decrease in FGFR3-TACC3 levels, compound 5a suppressed the growth of FGFR3-TACC3 positive cells. Thus, compound 5a is a candidate therapeutic with a novel drug modality against cancers that exhibit FGFR3-TACC3-dependent proliferation and exerts pharmacological effects distinct from FGFR3 kinase inhibitors because it lacks substructures crucial for kinase inhibition.
Insights
A new compound, SNIPER(TACC3)-11 (5a), effectively reduces FGFR3-TACC3 oncoprotein levels in cancer cells. This novel therapeutic approach targets FGFR3-TACC3-driven cancers, offering an alternative to kinase inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3) is a key oncogenic driver in various cancers, including glioblastoma and bladder cancer.
- Constitutive FGFR signaling activation by FGFR3-TACC3 leads to uncontrolled cell proliferation.
- Resistance to current FGFR tyrosine kinase inhibitors is a significant clinical challenge.
Purpose of the Study:
- To develop a novel therapeutic agent targeting FGFR3-TACC3.
- To investigate the mechanism of action of the developed compound.
- To evaluate the efficacy of the compound in inhibiting cancer cell growth.
Main Methods:
- A chimeric molecule, SNIPER(TACC3)-11 (5a), was synthesized by conjugating a TACC3 ligand (KHS108) to an inhibitor of apoptosis protein (IAP) ligand (LCL161 derivative) via a PEG linker.
- Mechanistic studies were performed to elucidate the role of cellular IAP1 in FGFR3-TACC3 reduction.
- The anti-proliferative effects of compound 5a on FGFR3-TACC3-positive cancer cells were assessed.
Main Results:
- Compound 5a effectively reduced FGFR3-TACC3 protein levels in cancer cells.
- Cellular IAP1 was identified as essential for the observed reduction in FGFR3-TACC3.
- Compound 5a demonstrated significant suppression of growth in FGFR3-TACC3-dependent cancer cells.
- The compound's mechanism of action is distinct from traditional FGFR3 kinase inhibitors.
Conclusions:
- SNIPER(TACC3)-11 (5a) represents a promising therapeutic candidate for cancers driven by FGFR3-TACC3.
- This novel drug modality offers a distinct pharmacological approach compared to existing kinase inhibitors.
- Further investigation is warranted to explore the clinical potential of compound 5a in treating FGFR3-TACC3-driven malignancies.
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