Protein c-Myb is a therapeutic target. Some sesquiterpene lactones suppress Myb-dependent gene expression, which results in a mechanism for their potential anti-cancer activity. Database ChEMBL is representative of lactones for physicochemical and physiochemical properties. Data presented for 31 natural lactones are discussed in terms of quantitative structure–activity relationships, which objective is to predict inhibitors of Myb-induced gene expression. Several constitutional descriptors are related to structure–activity. a‑Methylene‑g‑lactone groups enhance while OH functions worsen potency. The latter feature is in agreement  with the fact that the more lipophilic the lactone, the greater the cytotoxicity because of the ability to cross lipoidal biomembranes. In general, numbers of p-systems and atoms, and polarizability enhance activity. Linear and nonlinear structure–activity models are developed, between lactones of a great structural diversity, to predict inhibitors of Myb-induced gene expression. Four variables (ML, UNC, TCO+OCOR, UNC+UNA) related to ATOM show a positive correlation because of the partial anionic and H-acceptor characters of O-atom. In most, CO group is conjugated. Term OH shows negative coefficients because of the partial cationic quality of H-atom and because OH forms H-bonds with CO, causing them to be less H-acceptor. s‑trans‑s‑trans‑Germacranolide structure is the most active. Coefficients standard errors result acceptable in almost all equations. After cross-validation, linear equations for lactones, pseudoguaianolides and germacranolides are the most predictive. Most descriptors are constitutional variables.