Methionine aminopeptidase type 2 (MetAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. MetAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of MetAP2-specific substrates whose biological activity may be altered following MetAP2 inhibition, and additionally, that MetAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of MetAP2 using fumagillin analogs has established the anti-angiogenic and anti-tumor characteristics of these derivatives, however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting CNS toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel MetAP2 inhibitor (MetAP2i) SDX-7539. In vitro binding, enzyme and cell-based assays demonstrated that SDX-7539 is a potent and selective MetAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, MetAP2i SDX-7539, limitations observed with prior generation, small-molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the MetAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a Phase 1 clinical safety study in late-stage cancer patients and is currently being evaluated in multiple Phase 1b/2 clinical studies in patients with advanced solid tumors.

中文翻译：

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SDX-7320/Evexomostat 的药理学表征：具有抗肿瘤和抗转移活性的新型 2 型蛋氨酸氨基肽酶抑制剂

2 型蛋氨酸氨肽酶 (MetAP2) 是一种普遍存在的、进化上保守的金属蛋白酶，是蛋白质生物合成的基础，可催化去除新生多肽中的 N 端蛋氨酸残基。 MetAP2 是癌症治疗的一个有吸引力的靶点，因为它在多种人类癌症中过度表达，MetAP2 特异性底物的重要性，其生物活性可能在 MetAP2 抑制后改变，此外，MetAP2 被确定为抗肿瘤药物的靶点。血管生成天然产物，夫马洁林。使用夫马洁林类似物对 MetAP2 的不可逆抑制已经确立了这些衍生物的抗血管生成和抗肿瘤特性，然而，由于较差的类药特性和剂量限制性中枢神经系统毒性，它们的全部临床潜力尚未实现。本报告描述了 SDX-7320 (evexomostat) 的理化和药理学特征，SDX-7320 是新型 MetAP2 抑制剂 (MetAP2i) SDX-7539 的聚合物-药物缀合物。体外结合、酶和基于细胞的测定表明 SDX-7539 是一种有效的选择性 MetAP2 抑制剂。在利用高分子量水溶性聚合物缀合新型烟曲霉醇衍生、组织蛋白酶释放的 MetAP2i SDX-7539 时，上一代小分子烟曲霉醇衍生物的局限性得到了改善，包括减少了 MetAP2i 的 CNS 暴露，并且半衰期延长，方便给药。利用多个异种移植和同基因癌症模型来证明 SDX-7320 的抗肿瘤和抗转移特性。与一般的聚合物-药物缀合物不同，观察到聚合物缀合后小分子当量有效剂量的减少。 SDX-7320已完成针对晚期癌症患者的1期临床安全性研究，目前正在晚期实体瘤患者的多项1b/2期临床研究中进行评估。