Penipentenone A and brefeldin A derivatives potently inhibit KRAS mutant cancer cells from an endophytic fungus Penicillium brefeldianum F4a.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is one of the most important carcinogenic factors in many solid tumors, which leads to the poor prognosis and therapy resistance of cancer. In order to develop direct or indirect KRAS inhibitors, one unique asymmetric dicyclopentenone penipentenone A, three undescribed brefeldin A (BFA) derivatives, and five known BFA derivatives were discovered from the endophytic fungus Penicillium brefeldianum guided by LC-MS/MS and cytotoxic activities. Their structures were elucidated by optical rotation, mass spectrometry, and NMR spectroscopic data. The absolute configurations of four undescribed compounds were elucidated by comparison of the experimental and calculated ECD spectra. The antiproliferative activities of obtained compounds against three KRAS mutant tumor cell lines and two BFA derivative-sensitive cell lines were evaluated. Besides 4-epi-15-epi-brefeldin A, the other compounds showed significant inhibitory activities against those tumor cell lines with IC values ranging from 0.82 to 18.87 μM. Intriguingly, penipentenone A selectively inhibited KRAS mutant cancer cells SW620 (KRAS) and ASPC-1 (KRAS). BFA and four derivatives showed potent cytotoxic activities against all selected tumor cell lines H358 (KRAS), SW620 (KRAS), ASPC-1 (KRAS), PC-3, and HepG-2. These findings will provide undescribed lead compounds for developing drugs that target KRAS mutations.