Impact of the Smoothened inhibitor, IPI-926, on smoothened ciliary localization and Hedgehog pathway activity.
Impact of the Smoothened inhibitor, IPI-926, on smoothened ciliary localization and Hedgehog pathway activity.
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DOI：
10.1371/journal.pone.0090534
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Faia KL
中科院分区：
文献类型：
--
作者：
Peluso MO;Campbell VT;Harari JA;Tibbitts TT;Proctor JL;Whitebread N;Conley JM;White KF;Kutok JL;Read MA;McGovern K;Faia KL
通过Sonic Hedgehog（Shh）配体激活经典Hedgehog（Hh）途径的必要步骤是Smoothened（Smo）向初级纤毛（PC）的积累。Hh通路的激活已经涉及广泛的癌症，并且几种Smo拮抗剂正在临床上进行评估，其中一种被批准用于治疗晚期基底细胞癌。最近的报道表明，各种Smo拮抗剂差异影响Smo定位到PC，同时仍然发挥抑制活性。与其他合成的小分子Smo拮抗剂相反，天然产物环巴胺结合并促进Smo的纤毛积累，并在化合物停药后“引发”Hh途径高反应性细胞。我们比较了IPI-926（一种半合成的环巴胺类似物）与环巴胺在化合物停药后的效力、纤毛Smo积累和Hh途径活性方面的性质。与环巴胺一样，IPI-926促进Smo向PC的积累。然而，与环巴胺相反，IPI-926处理在化合物停药后没有引发细胞对Shh刺激的高反应性，而是表现出对信号传导的连续抑制。通过比较药物诱导的睫状体Smo积累的水平与化合物戒断后Hh途径活性的程度，我们提出睫状体Smo的临界阈值是发生“引发”活性所必需的。这种“引发”似乎可以用环巴胺而不是IPI-926实现，并且是细胞系依赖性的。此外，在鼠肿瘤异种移植模型中评价IPI-926活性，并检查药代动力学/药效学关系以评估Hh途径高反应性的体内证据。IPI-926的血浆浓度与Hh通路抑制的程度和持续时间相关，并且通路活性在给药后96小时内未超过基线水平。总体研究结果表明，IPI-926具有独特的生物物理和药理学特性，导致Hh途径抑制的方式，区分它从环巴胺。
A requisite step for canonical Hedgehog (Hh) pathway activation by Sonic Hedgehog (Shh) ligand is accumulation of Smoothened (Smo) to the primary cilium (PC). Activation of the Hh pathway has been implicated in a broad range of cancers, and several Smo antagonists are being assessed clinically, one of which is approved for the treatment of advanced basal cell carcinoma. Recent reports demonstrate that various Smo antagonists differentially impact Smo localization to the PC while still exerting inhibitory activity. In contrast to other synthetic small molecule Smo antagonists, the natural product cyclopamine binds to and promotes ciliary accumulation of Smo and “primes” cells for Hh pathway hyper-responsiveness after compound withdrawal. We compared the properties of IPI-926, a semi-synthetic cyclopamine analog, to cyclopamine with regard to potency, ciliary Smo accumulation, and Hh pathway activity after compound withdrawal. Like cyclopamine, IPI-926 promoted accumulation of Smo to the PC. However, in contrast to cyclopamine, IPI-926 treatment did not prime cells for hyper-responsiveness to Shh stimulation after compound withdrawal, but instead demonstrated continuous inhibition of signaling. By comparing the levels of drug-induced ciliary Smo accumulation with the degree of Hh pathway activity after compound withdrawal, we propose that a critical threshold of ciliary Smo is necessary for “priming” activity to occur. This “priming” appears achievable with cyclopamine, but not IPI-926, and is cell-line dependent. Additionally, IPI-926 activity was evaluated in a murine tumor xenograft model and a pharmacokinetic/pharmacodynamic relationship was examined to assess for in vivo evidence of Hh pathway hyper-responsiveness. Plasma concentrations of IPI-926 correlated with the degree and duration of Hh pathway suppression, and pathway activity did not exceed baseline levels out to 96 hours post dose. The overall findings suggest that IPI-926 possesses unique biophysical and pharmacological properties that result in Hh pathway inhibition in a manner that differentiates it from cyclopamine.
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影响因子：
3.7
作者：
Wilson CW;Chen MH;Chuang PT
通讯作者：
Chuang PT
与抗肿瘤药物结合的人平滑受体的结构。
影响因子：
64.8
作者：
通讯作者：
--
CK1α和GRK2的声音刺猬依赖性磷酸化是纤毛积累和平滑激活所必需的。
影响因子：
9.8
作者：
Chen Y;Sasai N;Ma G;Yue T;Jia J;Briscoe J;Jiang J
通讯作者：
Jiang J
DOI：
10.1126/science.1179386
发表时间：
2009-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Yauch RL;Dijkgraaf GJ;Alicke B;Januario T;Ahn CP;Holcomb T;Pujara K;Stinson J;Callahan CA;Tang T;Bazan JF;Kan Z;Seshagiri S;Hann CL;Gould SE;Low JA;Rudin CM;de Sauvage FJ
通讯作者：
de Sauvage FJ
DOI：
10.1083/jcb.200907126
发表时间：
2009-11-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Milenkovic L;Scott MP;Rohatgi R
通讯作者：
Rohatgi R