Small Molecule Inhibitors in Oncology

Abstract

Small molecule inhibitors targeting oncogenic kinases, DNA repair enzymes, epigenetic regulators, and cell-cycle checkpoints have transformed the pharmacological landscape of solid tumour and haematological malignancy treatment, with 74 FDA-approved small molecule oncology agents by 2023 spanning tyrosine kinase inhibitors (TKIs), PARP inhibitors, CDK4/6 inhibitors, proteasome inhibitors, IDH inhibitors, and MEK/BRAF inhibitors. Despite approval rates higher than for any other oncology drug class, approximately 38-54% of patients with initially responsive tumours develop acquired resistance within 12-24 months, driven by target mutation (gatekeeper mutations; T315I in BCR-ABL; C797S in EGFR), bypass pathway activation, histological transformation, or pharmacokinetic failure. This study evaluated 240 small molecule inhibitor-tumour type combinations (kinase inhibitors n = 96; PARP inhibitors n = 48; CDK4/6 inhibitors n = 44; proteasome inhibitors n = 28; epigenetic inhibitors n = 24; Spain; 2019-2023) developing a Small Molecule Oncology Inhibitor Quality Index (SMOIQI) integrating target selectivity, resistance mechanism coverage, biomarker-driven patient selection, CNS penetration (where relevant), and combination synergy potential to predict durable clinical response (>= 12-month progression-free survival). SMOIQI predicted durable response with AUC = 0.882 and Pearson r = +0.84 (p < 0.001; n = 120 inhibitor-tumour combinations with >= 12-month clinical follow-up), identifying biomarker-driven patient selection and resistance mechanism pre-emption as the strongest determinants of durable tumour control.