Design and structure-activity relationship studies of marine-derived indolocarbazoles as potent PIM1 inhibitors for triple-negative breast cancer therapy.

Abstract

PIM1 has emerged as a compelling target for triple-negative breast cancer (TNBC), which lacks effective treatments. Through integrated virtual screening and in vitro validation, N6 was identified as a potent PIM1-active indolocarbazole lead, although its strong PKC inhibition indicated a limited selectivity window. Structural comparison of PIM1 and PKC ATP-binding pockets revealed differences, including the Phe644 region in PKCη, that could be exploited to reduce PKC binding. A deep-learning/genetic-algorithm workflow yielded P19, which retained potent PIM1 inhibition (IC50 = 3.6 nM) while showing lower cytotoxicity toward MCF-10A cells and reduced inhibition of PKCδ/ε/η relative to N6. In an orthotopic TNBC mouse model, P19 (25 mg/kg) achieved potent tumor growth inhibition (TGI = 66.3%). Mechanistically, P19 reduced PIM1-GBP1 association and GBP1 phosphorylation, suggesting that the PIM1/GBP1 axis may contribute to its cellular activity. Overall, P19 represents a promising PIM1-potent, PKC-sparing multi-kinase lead for further TNBC optimization.