Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor

Abstract

The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third‐generation EGFR‐tyrosine kinase inhibitor (EGFR‐TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR‐TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor‐like biological activity of lamellarin N into kinase inhibitor‐like activity. Ba/F3 and PC‐9 cells expressing the EGFR in‐frame deletion within exon 19 (del ex19)/T790M/C797S triple‐mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple‐mutant EGFR PC‐9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple‐mutant EGFR PC‐9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR‐TKI that prevents the development of cross‐resistance against known drugs in this class.

Smart Polymeric Nanoparticles in Cancer Immunotherapy

“…Fucoidan is referred to as fucoidan sulfate derived from brown algae and echinoderms [ 173 ]. It is one of the most important marine drugs currently being developed due to its ability to inhibit the growth of tumor cells and treat cancer [ 174 ]. Fucoidan, a known immunomodulator, may be used as an adjuvant in the induction of anticancer immunity in animals and humans [ 175 ].…”

Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review

“…This compound was tested against the EGFR C797S and showed effective inhibition. 115 The double or triple mutations of EGFR C797S resistant to osimertinib (8) were inhibited by the bis(N,N-dimethylethanamine)ether derivative compound (51) in a specic manner. It also reduced downstream signal transduction and EGFR phosphorylation in triplet mutant EGFR PC-9 cells.…”

Marine Alkaloids: Compounds with In Vivo Activity and Chemical Synthesis

“…Another relevant synthetic derivative from marine alkaloids with anticancer potential is lamellarin 14 (inspired by naturally occurring lamellarins from mollusk Lamellaria sp. ; compound 7 ) [ 18 ]. This compound reduced the growth of adenocarcinoma in vivo after 17 days of treatment without significant loss of weight.…”