The marine-derived pachycladin diterpenoids as novel inhibitors of wild-type and mutant EGFR.

Epidermal growth factor receptor (EGFR) is a key player in proliferation and metastasis of various cancers. Discovery of novel EGFR inhibitors is still an urgent clinical oncology unmet need. Pachycladins are eunicellin-based diterpenoids isolated from the soft coral Cladiella pachycladous species. This study evaluated the anticancer activity of pachycladins A-E against diverse breast and cervical cancer cells. Pachycladin A (1) potently inhibited the proliferation of multiple cancer cell lines, without being cytotoxic to non-cancerous cells. The antiproliferative activity of 1 is mediated through cytostatic mechanisms rather than inducing apoptosis, as evidenced by lack of TUNEL response. Additionally, 1 arrested cell cycle in either G1 or G2/M phase, according to the cancer type, which induced caspase-dependent and independent apoptosis only after prolonged treatment. Meanwhile, 1 potently decreased microvessel formation and endothelial cell migration, suggesting its potential antiangiogenic activity. Different kinase profiling platforms revealed the exquisite potency and selectivity of 1 towards EGFR, even compared to other members of the EGFR family. In cancer cells, the antiproliferative activity of 1 was associated with suppression of EGFR activation and its downstream effectors. Interestingly, 1 significantly inhibited the drug-resistant T790M EGFR mutant, which is believed to be an attractive feature of EGFR inhibitors. Docking studies characterized the structural determinants required for efficient wild and mutant EGFR inhibition. Overlay studies of 1 with known EGFR inhibitors provided future guidance to chemically improve its binding affinity. Together, the anticancer activity of 1 is mediated by direct effects on tumor growth and angiogenesis, selectively via deactivating EGFR signaling, providing an excellent scaffold to control EGF-dependent cancers.