"Insilico Medicine publishes AI-driven innovative design strategy for highly selective FGFR2/3 inhibitors"
"Aberrations in fibroblast growth factor receptors FGFR2/3 are major drivers of many cancers—including intrahepatic cholangiocarcinoma, endometrial, breast, gastric, and bladder cancers. However, the development of selective inhibitors targeted FGFR2/3 has long been challenged by the high sequence and structural similarity among FGFR family members, particularly the binding pocket homology among FGFR1, FGFR2, and FGFR3 exceeds 95%.
Currently approved pan-FGFR inhibitors lack selectivity and often inhibit FGFR1/4 as well, leading to dose-limiting toxicities such as hyperphosphatemia and diarrhea, reduced treatment efficacy. Compounding these challenges, the emergence of resistance-conferring mutations in FGFR2/3 frequently diminishes the effectiveness of current drugs."
"The Chemistry42 platform was leveraged to generate a library of approximately 10,000 molecules with diverse core structures and linkers, prioritizing those predicted to exhibit strong protein-ligand interactions (as measured by PLI score) and favorable drug-like properties. Based on the generated amide-based scaffold, we found that flexible binding to the kinase hinge region can better accommodate various types of resistance mutations. By filtering for optimal molecular characteristics and high PLI scores, the team identified core3 (C3) as a structural motif likely to deliver high potency and selectivity for FGFR2/3.
Further ADMET prediction and Alchemistry—the free energy calculations module of Chemistry42—were subsequently used to rank and optimize the candidate molecules. This process ultimately led to the identification of ISM7594, a covalent dual FGFR2/3 inhibitor distinguished by its unique hinge-binding motif and novel core structure.
In the validation studies, ISM7594 exhibits nanomolar inhibitory activity against FGFR2 and FGFR3, with over 100-fold selectivity relative to FGFR1/4. It maintained strong efficacy against clinically relevant FGFR2/3 mutants associated with therapeutic resistance. In cancer cell lines harboring FGFR2/3 alterations, ISM7594 showed robust antiproliferative effects, while exhibiting minimal impact on cells without FGFR aberrations. In preclinical animal models, ISM7594 displayed favorable pharmacokinetic properties, significant tumor growth inhibition, and a reduced toxicity profile compared to less selective FGFR inhibitors."
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