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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
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,Giacomini Adoi
10.1016/j.ejmech.2021.113529keywords:
["FGF-Trap","FGF2","Fibroblast growth factor","Multiple myeloma","NSC12"]subject
Has Abstractpub_date
2021-10-05 00:00:00pages
113529eissn
0223-5234issn
1768-3254pii
S0223-5234(21)00378-0journal_volume
221pub_type
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