2. Academic Validation
  3. Chemical modification of NSC12 leads to a specific FGF-trap with antitumor activity in multiple myeloma

Chemical modification of NSC12 leads to a specific FGF-trap with antitumor activity in multiple myeloma

  • Eur J Med Chem. 2021 Oct 5:221:113529. doi: 10.1016/j.ejmech.2021.113529.
Riccardo Castelli 1,  Sara Taranto 2,  Lucia Furiassi 3,  Nicole Bozza 1,  Giuseppe Marseglia 1,  Francesca Ferlenghi 1,  Silvia Rivara 4,  Michele Retini 3,  Annalida Bedini 3,  Gilberto Spadoni 3,  Sara Matarazzo 2,  Roberto Ronca 2,  Marco Presta 2,  Marco Mor 1,  Arianna Giacomini 2
Affiliations

Affiliations

  • 1 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
  • 2 Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, via Branze 39, I-25123, Brescia, Italy.
  • 3 Dipartimento di Scienze Biomolecolari, Università, degli Studi di Urbino "Carlo Bo", Piazza Rinascimento 6, I-61029, Urbino, Italy.
  • 4 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124, Parma, Italy. Electronic address: silvia.rivara@unipr.it.
PMID: 34004471 DOI: 10.1016/j.ejmech.2021.113529
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.

Keywords

FGF-Trap; FGF2; Fibroblast growth factor; Multiple myeloma; NSC12.

Figures