FGFR2/3

FGFR2/3 Dual Inhibitor: Treatment of Solid Tumors

(IND-Enabling)

Assays Completed

• In vivo efficacy studies
• In vivo PK-PD
• In vivo PK studies
• In vitro ADMET studies
• In vitro cell-based
• Toxicology studies
• Enzymatic

Target Rationale

FGFR2/3 inhibitors target the fibroblast growth factor receptors 2, and 3. The FGFR2/3 signaling pathway is involved in cell growth, survival, migration, and angiogenesis, and can be abnormally activated in some cancers due to genetic alterations in FGFR genes. Insilico Medicine inhibitor binds to the kinase domain of FGFR2/3 thereby blocking their activity. Inhibition of FGFR2/3 is caused by reducing the phosphorylation of FGFRs and their downstream targets. By blocking FGFR signaling, FGFR2/3 inhibitors aim to stop or slow down the growth and spread of cancer cells. FGFR2/3 inhibitors are currently being tested in clinical trials for various types of cancers, such as bladder, breast, lung, and bile duct cancers.

Insilico Medicine FGFR2/3 Dual Inhibitor Summary – IND-Enabling

• Novel structure generated by AI: Novel structure generated by Insilico Medicine's AI small molecule generation platform Chemistry 42
• Effective therapy for treating solid tumors:
  • Offers high selectivity over FGFR1/4 inhibitors to avoid severe dose-limiting AEs, e.g. hyperphosphatemia, diarrhea
  • Broader indication scope covering patients with FGFR2 or FGFR3 alterations

Promising drug-ability as an oral agent

• Favorable DMPK profile with higher permeability, low efflux ratio, and good oral bioavailability across preclinical species
• Low drug-drug interaction concerns, good drug-likeness with good solubility, and low efficacious dose

Significantly higher safety margin

• Overall good tolerability up to high doses in rodent and dog models based on DRF studies
• Exhibits favorable PK profiles across different preclinical animal species (low CL, high F%, and high AUC) along with safety profiles

Indication

Dual inhibitor for treating solid tumors

• FGFR2/3 dual inhibitor offers more effective target inhibition, in vivo efficacy, and druggability as an oral single agent, with significantly higher safety margins
• FGFR2/3 inhibitor is highly selective and offers potent and broad-spectrum activity against mutations in both the FGFR2, and FGFR3 kinase domains
• Irreversible covalent compound with high potency, selectivity, and prolonged target inhibition
• Potent anti-proliferation activity in multiple cancer cell lines

Project Highlight

ISM developed an AI-designed covalent inhibitor targeting FGFR2/3 with high selectivity over FGFR1/4 to avoid dose-limiting adverse effects, e.g. hyperphosphatemia, diarrhea and liver toxicity. The compound has broader indication scope covering patients with FGFR2/3 aberration and can overcoming acquired resistance to pan-FGFR inhibitor. Preclinical studies have demonstrated potential tissue-agnostic therapeutic options for FGFR2/3 altered tumors including UC, ICC, NSCLC, CRC and PDAC and showed favorable DMPK profiles, low efficacious dose, and desirable safety margin to support higher human dose.

No hyperphosphatemia observed in all groups treated with ISM8001.