Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124, Parma, Italy.
Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, via Branze 39, I-25123, Brescia, Italy.
Eur J Med Chem. 2021 Oct 5;221:113529. doi: 10.1016/j.ejmech.2021.113529. Epub 2021 May 5.
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.
抑制 FGF/FGFR 信号通路是治疗依赖 FGF 刺激的恶性肿瘤的一种很有前途的策略，包括多发性骨髓瘤（MM）。甾体衍生物 NSC12（化合物 1）是一种泛 FGF 陷阱，具有体内抗肿瘤活性。对化合物 1 进行了化学修饰，以研究构效关系，重点研究了双（三氟甲基）1,3-丙二醇链、C20 立体化学和 C3 位置功能化的作用。我们的研究揭示了化合物 25b，即化合物 1 的孕烷 3-酮 20R 衍生物，是一种有效的药物，通过抑制 FGF 依赖性受体激活来阻止 MM 细胞的增殖，并减缓 MM 在体内的生长。重要的是，C3 上的羟基缺失可防止与雌激素受体结合，这可能有助于观察到化合物 1 的抗肿瘤活性，导致一种特定的 FGF/FGFR 系统抑制剂，并进一步支持 FGFR 在 MM 中抗癌治疗中的作用。
