1. Chemical modification of NSC12 leads to a specific FGF-trap with antitumor activity in multiple myeloma.
- Author
-
Castelli R, Taranto S, Furiassi L, Bozza N, Marseglia G, Ferlenghi F, Rivara S, Retini M, Bedini A, Spadoni G, Matarazzo S, Ronca R, Presta M, Mor M, and Giacomini A
- Subjects
- Animals, Antineoplastic Agents, Cell Proliferation drug effects, Cell Survival drug effects, Cholesterol analogs & derivatives, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Fibroblast Growth Factors metabolism, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Structure, Multiple Myeloma metabolism, Multiple Myeloma pathology, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Structure-Activity Relationship, Tumor Cells, Cultured, Fibroblast Growth Factors antagonists & inhibitors, Multiple Myeloma drug therapy
- Abstract
Inhibition of FGF/FGFR signaling is a promising strategy for the treatment of malignances dependent from FGF stimulation, including multiple myeloma (MM). The steroidal derivative NSC12 (compound 1) is a pan-FGF trap endowed with antitumor activity in vivo. Chemical modifications of compound 1 were explored to investigate structure-activity relationships, focusing on the role of the bis(trifluoromethyl)1,3-propanediol chain, the stereochemistry at C20 and functionalization of C3 position. Our studies unveiled compound 25b, the pregnane 3-keto 20R derivative of compound 1 as an effective agent, blocking the proliferation of MM cells in vitro by inhibiting FGF-dependent receptor activation and slowing MM growth in vivo. Importantly, the absence of the hydroxyl group at C3 prevents binding to estrogen receptors, which might concur to the antitumor activity observed for compound 1, leading to a specific FGF/FGFR system inhibitor, and further supporting the role of FGFR in anticancer therapy in MM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF