Enzalutamide and Apalutamide: In Vitro Chemical Reactivity Studies and Activity in a Mouse Drug Allergy Model.,Chemical Research in Toxicology

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Enzalutamide and Apalutamide: In Vitro Chemical Reactivity Studies and Activity in a Mouse Drug Allergy Model.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-10-09 , DOI: 10.1021/acs.chemrestox.9b00247
Changhua Ji ₁ , Mausumee Guha ₁ , Xu Zhu ₂ , Jessica Whritenour ₂ , Michelle Hemkens ₁ , Susanna Tse ₃ , Gregory S Walker ₃ , Ellen Evans ₂ , Nasir K Khan ₄ , Martin B Finkelstein ₄ , Ernesto Callegari ₃ , R Scott Obach ₃

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Enzalutamide and apalutamide are two androgen receptor inhibitors approved for the treatment of castration-resistant prostate cancer (CRPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC), respectively. Apalutamide is associated with an increased incidence of skin rash above the placebo groups in the SPARTAN trial in nmCRPC and in the TITAN trial in metastatic castration-sensitive prostate cancer patients. On the contrary, the rate of skin rash across all clinical trials (including PROSPER [nmCRPC]) for enzalutamide is similar to the placebo. We hypothesized that the apalutamide-associated increased skin rash in patients could be linked to a structural difference. The 2-cyanophenyl and dimethyl moieties in enzalutamide are substituted in apalutamide with 2-cyanopyridine and cyclobutyl, respectively. In our evaluations, the 2-cyanopyridine moiety of apalutamide was chemically reactive with the thiol nucleophile glutathione, resulting in rearranged thiazoline products. Radiolabeled apalutamide, but not radiolabeled enzalutamide, was shown to react with mouse and human plasma proteins. Thiol nucleophiles decreased the extent of covalent binding to the model protein bovine serum albumin, whereas amine and alcohol nucleophiles had no effect, suggesting reactivity with cysteine of proteins. Subcutaneous administration of apalutamide dose dependently increased lymphocyte cellularity in draining lymph nodes in a mouse drug allergy model (MDAM). Enzalutamide, and its known analogue RD162 in which the cyanophenyl was retained but the dimethyl was replaced by cyclobutyl, demonstrated substantially less covalent binding activity and negative results in the MDAM assay. Collectively, these data support the hypothesis that the 2-cyanopyridine moiety in apalutamide may react with cysteine in proteins forming haptens, which may trigger an immune response, as indicated by the activity of apalutamide in the MDAM assay, which in turn may be leading to increased potential for skin rash versus placebo in patients in the SPARTAN and TITAN clinical trials.

中文翻译：

Enzalutamide和Apalutamide：小鼠药物过敏模型中的体外化学反应性研究和活性。

Enzalutamide和apalutamide是分别批准用于治疗去势抵抗性前列腺癌（CRPC）和非转移性去势抵抗性前列腺癌（nmCRPC）的两种雄激素受体抑制剂。在nmCRPC的SPARTAN试验和转移性去势敏感性前列腺癌患者的TITAN试验中，阿帕鲁胺与高于安慰剂组的皮疹发生率增加相关。相反，恩杂鲁胺在所有临床试验（包括PROSPER [nmCRPC]）中的皮疹发生率与安慰剂相似。我们假设患者与阿帕鲁胺相关的皮疹增加可能与结构差异有关。enzalutamide中的2-氰基苯基和二甲基部分在apalutamide中分别被2-氰基吡啶和环丁基取代。在我们的评估中 apalutamide的2-cyanopyridine部分与巯基亲核体谷胱甘肽发生化学反应，从而导致重排的噻唑啉产物。放射性标记的apalutamide，而不是放射性标记的enzalutamide，已显示与小鼠和人类血浆蛋白反应。硫醇亲核试剂降低了与模型蛋白牛血清白蛋白的共价结合程度，而胺和醇亲核试剂则没有作用，表明与蛋白的半胱氨酸具有反应性。在小鼠药物过敏模型（MDAM）中，皮下注射阿帕鲁胺剂量依赖地增加了引流淋巴结中的淋巴细胞细胞数量。Enzalutamide及其已知的类似物RD162（其中保留了氰基苯基，但二甲基被环丁基取代）在MDAM分析中显示出显着较低的共价结合活性，并且阴性。

更新日期：2019-10-10

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