Structure-Based Design of a Novel Covalent 4-(1-Methylindol-3-yl)pyrimidin-2-amine Series Targeting FGFR2 Resistance
Robert L Hudkins1, Eric Allen1, Samhita Iyer1
1Tyra Biosciences, Inc., 2656 State Street, Carlsbad, California 92008, United States.
Abstract:
Genetic alterations in FGFR2 drive multiple malignancies, most notably intrahepatic cholangiocarcinoma, where they occur in ∼10-15% of patients. While approved pan-FGFR inhibitors provide clinical benefit, their durability is limited by acquired, often polyclonal, on-target resistance mutations affecting key regions of the FGFR2 kinase domain, including the gatekeeper residue (V565), molecular brake residues (N550, E566, K642), and other key variants. These liabilities motivate the development of next-generation inhibitors. Given FGFR2-associated toxicities and the need for subtype selectivity, FGFR4 inhibition was prioritized as a selectivity determinant, while sparing FGFR1 was considered less critical. Guided by structure-based drug design, a reversible aminopyrimidine screening hit was optimized into a novel covalent inhibitor series active against FGFR2 wild-type and clinically relevant resistance mutations. An advanced lead 13 showed favorable potency, ADME properties, and demonstrated proof-of-concept in vivo efficacy in an FGFR2-amplified xenograft model comparable with the standard of care.
Insights
Next-generation FGFR2 inhibitors combat resistance mutations in intrahepatic cholangiocarcinoma. A novel covalent inhibitor demonstrated potent activity against FGFR2 wild-type and resistant forms, showing promise in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Fibroblast Growth Factor Receptor 2 (FGFR2) genetic alterations drive malignancies like intrahepatic cholangiocarcinoma (ICC).
- Approved pan-FGFR inhibitors offer clinical benefit but face limited durability due to acquired resistance mutations in FGFR2 kinase domain.
- Development of next-generation inhibitors is crucial to overcome resistance and improve treatment outcomes.
Purpose of the Study:
- To develop novel covalent inhibitors targeting FGFR2, including those with resistance mutations.
- To achieve selectivity for FGFR4 while sparing FGFR1, addressing FGFR2-associated toxicities.
- To evaluate the preclinical efficacy of a novel inhibitor series in relevant cancer models.
Main Methods:
- Structure-based drug design was employed to optimize a screening hit into a novel covalent inhibitor series.
- In vitro assays assessed inhibitor activity against wild-type and resistant FGFR2 mutations.
- Pharmacokinetic (ADME) properties and in vivo efficacy were evaluated in an FGFR2-amplified xenograft model.
Main Results:
- A novel covalent inhibitor series demonstrated potent activity against FGFR2 wild-type and key resistance mutations.
- Lead compound 13 exhibited favorable potency and ADME properties.
- Proof-of-concept in vivo efficacy was achieved in an FGFR2-amplified xenograft model, comparable to the standard of care.
Conclusions:
- The developed covalent inhibitors are active against FGFR2, including clinically relevant resistance mutations.
- Lead compound 13 shows potential as a next-generation therapeutic for FGFR2-driven malignancies.
- This study provides a foundation for further development of selective FGFR inhibitors.
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