Abstract B067: Discovery of a highly potent and selective covalent FGFR3 inhibitor

Abstract Fibroblast growth factor receptors (FGFR1-4) are a family of receptor tyrosine kinases that play crucial roles in regulating cell growth, survival, and differentiation. Aberrant activation of FGFR signaling is a well-established oncogenic driver across multiple cancer types, promoting key cancer hallmarks including proliferation, survival, angiogenesis, invasion, and metastasis. While pan-FGFR and subtype-selective inhibitors have demonstrated clinical benefits, their efficacy is often constrained by on-target toxicities - including hyperphosphatemia, gastrointestinal and ocular side effects, and hepatotoxicity – primarily resulting from inhibition of FGFR1/2/4. Notably, no FGFR3-specific toxicities have been identified, making selective inhibition of FGFR3 an attractive strategy for treating FGFR3-driven cancers. Despite this potential, FGFR3 remains an underexploited therapeutic target with few approved treatments for FGFR3-driven cancers and none for non-urothelial malignancies harboring FGFR3 alterations. Among emerging agents, LOXO-435 stands out as the most selective FGFR3 inhibitor in clinical trials, showing best-in-class safety and efficacy to date. This highlights a significant unmet medical need and a compelling opportunity for selective FGFR3-targeted therapeutics. We identified covalent small molecules that selectively bind to FGFR3 at its unique Cysteine site. Through structure–activity relationship (SAR), we developed BGP-31172—a first-generation lead molecule that is a covalent FGFR3 inhibitor with high potency and exceptional selectivity across the FGFR family. BGP-31172 potently inhibited FGFR3 phosphorylation in KMS-11 cells (FGFR3Y373C), with an IC50 of 2.5 ± 0.8 nM (n = 3), showing over 47-fold selectivity versus FGFR2 phosphorylation in KATOiii cells (FGFR2 fusion, n=3). Compared to LOXO-435 (active compound from Example 1, WO2024054814) (IC50 = 5.8± 1.1 nM; 25-fold selectivity, n=9), BGP-31172 demonstrated superior potency and selectivity. In Ba/F3 cells expressing ETV6-FGFR3, BGP-31172 exhibited strong anti-proliferative activity (CTG IC50 = 0.2 nM), with 450-, 47-, and 613-fold selectivity over Ba/F3 cells driven by FGFR1, FGFR2, and FGFR4 fusions, respectively. BGP-31172 retained potency against the FGFR3V555M gatekeeper mutation. Across FGFR-driven Ba/F3 models, BGP-31172 consistently outperformed LOXO-435 (IC50 = 10.9 nM; 244-, 14-, and 205-fold selectivity vs. FGFR1/2/4, respectively). In cancer cell lines, BGP-31172 robustly inhibited growth of RT112/84 cells (FGFR3-TACC3 fusion) with an IC50 of 0.7 nM, markedly more potent than LOXO-435 (IC50 = 16.3 nM). In contrast, BGP-31172 showed >1300-fold reduced potency in FGFR3-independent T24 bladder cancer cells, confirming its strong pathway selectivity. BGP-31172 demonstrates exceptional potency and selectivity as a covalent FGFR3 inhibitor, with strong in vitro activity across FGFR3-driven cancer models. BridGene is actively optimizing this promising compound series to meet the urgent clinical need in FGFR3-altered malignancies. Citation Format: Vivian Zhang, Hiroko Tanaka, Shanshan Deng, Iris Dong, Nikolas Burton, Logan Schachtner, Yining Hao, Ning Deng, Petr Jansa, Anna Chen, Ping Cao, Shirley Guo. Discovery of a highly potent and selective covalent FGFR3 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B067.