Quantitative SAR of Oleanolic Acid Derivatives at the Kinase–Phosphatase Interface: PTP1B Selectivity and RTK Pharmacology in Cancer

Oleanolic acid (OA) is readily modified at C-3 and C-28, but mechanistic studies of its derivatives often rely on downstream signaling readouts. This review examines compound series in which structural changes can be compared with quantitative enzyme data, receptor-level measurements, or functional target dependence, with emphasis on cancer pharmacology. PTP1B-directed studies show that potency and discrimination from the closely related TCPTP are separable SAR properties; later glycoside series changed the PTP1B/TCPTP selectivity profile, while cellular anticancer activity varied independently. Among RTKs, matched C-28 phenylurea derivatives have quantitative VEGFR2 inhibition data, whereas K73-03 has an EGFR-dependent cellular phenotype supported by molecular modeling, receptor phosphorylation, EGFR knockdown, and xenograft experiments. OA dimers show linker- and C-3-acetylation-dependent cellular SAR, while FAK remains a docking-derived target hypothesis without direct kinase validation. AKT/mTOR, AMPK/mTOR, JAK/STAT3, NF-κB, and Nrf2 responses are treated as downstream context unless supported by upstream target evidence. The compounds discussed here remain preclinical, and further development requires matched subtype profiling, direct receptor assays, functional target-dependence experiments, and compound-specific pharmacokinetic evaluation.