成纤维细胞生长因子 (FGF) 在包括多发性骨髓瘤 (MM) 在内的多种癌症中充当促血管生成和促有丝分裂细胞因子。事实上，受损的 FGF 自分泌和旁分泌分泌会诱导 FGF 受体 (FGFR) 信号异常激活，从而维持癌细胞扩散和对药物治疗的抵抗。因此，FGF 陷阱可能代表一种有前途的抗癌策略，以阻碍 FGF/FGFR 系统的配体依赖性激活。我们之前发现 NSC12 是第一个口服小分子 FGF 捕获剂，能够抑制多种 FGF 依赖性肿瘤模型的生长和进展。 NSC12 是一种孕烯醇酮衍生物，在类固醇核的 17 位上带有 1,1-双-三氟甲基-1,3-丙二醇链。结构-活性关系 (SAR) 的研究提供了更有效和更特异的 NSC12 类固醇衍生物，并强调 C17 侧链对于 FGF 捕获活性至关重要。在这里，支架跳跃方法允许获得两种没有类固醇核的 FGF 捕获化合物（22 和 57），并且能够有效结合 FGF2 并抑制 MM 细胞中的 FGFR 激活。因此，这些化合物在体外和体内对MM细胞系以及MM患者来源的原代细胞发挥有效的抗肿瘤活性，强烈影响蛋白酶体抑制剂敏感和耐药的MM细胞的存活。这些结果为复发/难治性 MM 患者提出了一种新的治疗选择，并为开发易于化学多样化的新型 FGF 陷阱奠定了基础，用于临床治疗 FGF/FGFR 系统发挥关键作用的肿瘤角色，包括 MM。版权所有 © 2024。由 Elsevier Ltd 出版。

Fibroblast growth factors (FGFs) act as proangiogenic and mitogenic cytokines in several cancers, including multiple myeloma (MM). Indeed, corrupted FGF autocrine and paracrine secretion induces an aberrant activation of the FGF receptor (FGFR) signaling sustaining cancer cell spreading and resistance to pharmacological treatments. Thus, FGF traps may represent a promising anti-cancer strategy to hamper the ligand-dependent activation of the FGF/FGFR system. We previously identified NSC12 as the first orally available small molecule FGF trap able to inhibit the growth and progression of several FGF-dependent tumor models. NSC12 is a pregnenolone derivative carrying a 1,1-bis-trifluoromethyl-1,3-propanediol chain in position 17 of the steroid nucleus. Investigation of structure-activity relationships (SARs) provided more potent and specific NSC12 steroid derivatives and highlighted that the C17-side chain is pivotal for the FGF trap activity. Here, a scaffold hopping approach allowed to obtain two FGF trap compounds (22 and 57) devoid of the steroid nucleus and able to efficiently bind FGF2 and to inhibit FGFR activation in MM cells. Accordingly, these compounds exert a potent anti-tumor activity on MM cell lines both in vitro and in vivo and on MM patient-derived primary cells, strongly affecting the survival of both proteasome-inhibitor sensitive and resistant MM cells. These results propose a new therapeutic option for relapsed/refractory MM patients and set the bases for the development of novel FGF traps prone to chemical diversification to be used in the clinic for the treatment of those tumors in which the FGF/FGFR system plays a pivotal role, including MM.Copyright © 2024. Published by Elsevier Ltd.