Isoform-selective FGFR inhibition as pioneer in cancer therapy: heterocyclic scaffold optimization strategies, mechanistic insights, and future directions

INTRODUCTION: Fibroblast Growth Factor Receptor (FGFR) drives cell proliferation by triggering PI3K-AKT, JAK-STAT, MAPK, IP3-DAG, and RAS-RAF-MEK cascades, promoting lung, breast, prostate, and bladder cancers. Pan-selective FGFR inhibitors (SFGFRIs) are characterized by their ability to target multiple FGFR isoforms (FGFR1-4). Several heterocyclic pan-SFGFRIs have been approved by the FDA. Their lack of isoform-selectivity has raised adverse effects such as hyperphosphatemia, ocular and gastrointestinal toxicities, nail toxicities, and fatigue. Therefore, FGFR (1/2/3/4)-isoform-selective heterocyclic-FGFRIs have emerged as promising alternatives to reduce off-target effects and overcome drug resistance. AREAS COVERED: This review highlights mechanisms, advantages, limitations, and drug resistance of FDA-approved and clinical SFGFRIs. The in silico isoform-selectivity study provided insights into isoform-specific binding affinity, interactions, and mechanisms of SFGFRIs. Screening, classification, and scaffold-oriented structure-optimization strategies of promising heterocyclic SFGFRIs provided future-direction toward isoform-selectivity. EXPERT OPINION: Structure-activity-correlation study revealed pyrazole and indazole as FGFR1-targeted, pyridine and pyrimidine as dual FGFR1-2-targeted, and quinazoline as FGFR4-targeted privileged scaffolds. In silico evaluation highlighted the scarcity of pure FGFR1-selective inhibitors, while isoform-selectivity was demonstrated by resigratinib toward FGFR2 (-14.008 kcal/mol), tasurgratinib toward FGFR3 (-4.634 kcal/mol), and H3B-6527 toward FGFR4 (-5.162 kcal/mol). Collectively, the findings underscored isoform-selective FGFR inhibition as a vast avenue for exploration to deliver a paradigm-shift in oncology by addressing drug resistance and minimizing toxicities.