Respiratory Drug Discovery, Inflammation, Hoffmann-La Roche Inc., Nutley, NJ, USA.
Pharmacol Ther. 2012 Sep;135(3):279-91. doi: 10.1016/j.pharmthera.2012.06.001. Epub 2012 Jun 18.
Dysregulation of the transforming growth factor β (TGFβ) pathway has been implicated to underlie a number of disease indications including chronic lung disorders such as asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonias, and pulmonary arterial hypertension (PAH). Consequently, the pharmaceutical industry has devoted significant resources in the pursuit of TGFβ pathway inhibitors that target the cognate type I and II receptors and respective ligands. The progress of these approaches has been painfully slow, due in part to dose-limiting safety issues that result from the antagonism of a pathway that is responsible for regulating many fundamental biological processes including immune surveillance and cardiovascular responses. These disappointments have led many in the field to conclude that modulating the TGFβ pathway for chronic indications with a sufficient safety window using conventional approaches may be extremely difficult to achieve. Here we review the rationale and limitations of the use of TGFβ pathway inhibitors in chronic lung disorders and the possibility of targeting TGFβ superfamily ligand accessory proteins to allow rheostatic regulation of signaling to achieve efficacy while maintaining a sufficient therapeutic index.
转化生长因子 β（TGFβ）通路的失调与许多疾病的发生有关，包括哮喘、慢性阻塞性肺疾病（COPD）、间质性肺炎和肺动脉高压（PAH）等慢性肺部疾病。因此，制药行业投入了大量资源来研发靶向同源型 I 和 II 受体及相应配体的 TGFβ 通路抑制剂。然而，这些方法的进展非常缓慢，部分原因是由于拮抗负责调节许多基本生物过程（包括免疫监视和心血管反应）的通路而导致的剂量限制安全性问题。这些挫折导致该领域的许多人得出结论，即使用传统方法针对慢性疾病调节 TGFβ 通路以获得足够的安全性窗口可能极难实现。在这里，我们回顾了 TGFβ 通路抑制剂在慢性肺部疾病中的应用的原理和局限性，以及靶向 TGFβ 超家族配体辅助蛋白以实现信号传导的变阻器调节的可能性，从而在保持足够治疗指数的同时实现疗效。
