PTP1B Inhibitors for Type 2 Diabetes: From Natural Products, Synthetic Inhibitors, and Multi-Target Drug Design Strategies to Clinical Translation.

Type 2 Diabetes Mellitus (T2DM) still exists as a worldwide health problem, and the current therapeutic options have selectivity and bioavailability issues. Protein Tyrosine Phosphatase 1B (PTP1B) emerged as an important therapeutic target for T2DM. In this study, we analyzed all publications between 2021 and 2025 available in the Scopus database, and the search was limited to English-language articles that were also indexed in PubMed. The search strategy employed multiple keyword combinations, including "PTP1B" OR "Protein Tyrosine Phosphatase 1B" OR "PTPN1", combined with inhibitor, drug discovery, type 2 diabetes, insulin resistance, and structural biology terms. Natural products from plant, marine, and microbial sources demonstrate diverse PTP1B inhibitory mechanisms through their active compounds, which include terpenoids, flavonoids, alkaloids, and diarylheptanoids. The development of synthetic approaches that combine thiazole derivatives with coumarin-based compounds and peptide inhibitors has produced promising scaffolds. The researchers used computational methods to find new allosteric binding sites through molecular docking and molecular dynamics simulations. The four clinical candidates Ertirprotafib, Trodusquemine, ISIS-113715, and JTT-551 all failed because their selectivity and efficacy were insufficient, but the dual PTPN2/PTPN1 inhibitor ABBV-CLS-484 shows oncology treatment potential. Beyond diabetes, PTP1B inhibition shows medical value for cancer immunotherapy treatment, together with neurodegenerative disorders, inflammation, and cardiovascular diseases. The development of PROTAC degraders, glycosylation-lipidation modifications, and multi-target inhibitors represents a new approach to solving past problems. The development of PTP1B inhibitors requires integrated approaches that include allosteric modulation, tissue-specific delivery, and patient stratification to achieve successful clinical translation across multiple disease indications.