Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT, 06269, USA.
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, United States.
Eur J Med Chem. 2019 Feb 1;163:320-332. doi: 10.1016/j.ejmech.2018.11.056. Epub 2018 Nov 23.
Inhibition of the hedgehog (Hh) signaling pathway has been validated as a therapeutic strategy to treat basal cell carcinoma and holds potential for several other forms of human cancer. Itraconazole and posaconazole are clinically useful triazole anti-fungals that are being repurposed as anti-cancer agents based on their ability to inhibit the Hh pathway. We have previously demonstrated that removal of the triazole from itraconazole does not affect its ability to inhibit the Hh pathway while abolishing its primary side effect, potent inhibition of Cyp3A4. To develop structure-activity relationships for the related posaconazole scaffold, we synthesized and evaluated a series of des-triazole analogues designed through both ligand- and structure-based methods. These compounds demonstrated improved anti-Hh properties compared to posaconazole and enhanced stability without inhibiting Cyp3A4. In addition, we utilized a series of molecular dynamics and binding energy studies to probe specific interactions between the compounds and their proposed binding site on Smoothened. These studies strongly suggest that the tetrahydrofuran region of the scaffold projects out of the binding site and that π-π interactions between the compound and Smoothened play a key role in stabilizing the bound analogues.
抑制刺猬（Hh）信号通路已被验证为治疗基底细胞癌的一种治疗策略，并有可能用于治疗几种其他形式的人类癌症。伊曲康唑和泊沙康唑是临床上有用的三唑类抗真菌药物，由于其抑制 Hh 通路的能力，正在被重新用于抗癌药物。我们之前已经证明，从伊曲康唑中去除三唑部分不会影响其抑制 Hh 通路的能力，同时消除了其主要的副作用，即对 Cyp3A4 的强烈抑制。为了开发与泊沙康唑骨架相关的结构-活性关系，我们通过配体和基于结构的方法合成并评估了一系列去三唑类似物。与泊沙康唑相比，这些化合物表现出更好的抗 Hh 特性，并且在不抑制 Cyp3A4 的情况下增强了稳定性。此外，我们利用一系列分子动力学和结合能研究来探测化合物与其在 Smoothened 上的假定结合位点之间的特定相互作用。这些研究强烈表明，支架的四氢呋喃区域从结合位点伸出，化合物与 Smoothened 之间的π-π相互作用在稳定结合的类似物中起着关键作用。
