Department of Medicinal Chemistry , University of Kansas , Lawrence , Kansas 66047 , United States.
Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
J Med Chem. 2018 Jun 14;61(11):4946-4960. doi: 10.1021/acs.jmedchem.8b00419. Epub 2018 May 24.
Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects.
雄激素生物合成的抑制在治疗雄激素反应性前列腺癌方面具有临床疗效。阿比特龙是一种临床首创的细胞色素 P450 17A1（CYP17A1）抑制剂，用于雄激素生物合成。然而，阿比特龙也会引起高血压、低血钾和水肿，这可能部分归因于对另一种类固醇生成细胞色素 P450 CYP21A2 的非靶向抑制。阿比特龙类似物是基于结构证据设计的，即 B 环取代基可能与 CYP17A1 的极性残基有利相互作用，并与 CYP21A2 活性位点的残基发生空间冲突。与阿比特龙相比，最好的类似物将 CYP17A1 抑制的选择性提高了 84 倍，而提高了 6.6 倍。与 CYP17A1 的共结晶验证了与 CYP17A1 活性位点残基的预期新接触。将这些类似物对接入 CYP21A2 中，确定了可能导致结合和 CYP21A2 抑制减少的空间冲突。总的来说，这些类似物可能会以减少副作用的形式提供临床优势。
