VERDINE, GREGORY LAWRENCE,佛丹 格列格里 罗伦斯,佛丹 格列格里 羅倫斯,NICHOLS, MATTHEW JAMES,尼可 马修 詹姆斯,尼可 馬修 詹姆斯,STILES, DYLAN TALBOT,斯提尔 迪兰 塔波特,斯提爾 迪蘭 塔波特,ANTHONY, NEVILLE JOHN,安东尼 奈维尔 约翰,安東尼 奈維爾 約翰,BOWMAN, BRIAN ROGER
申请号：
TW105100137
公开号：
TW201629069A
申请日:
2016.01.05
申请国别(地区):
TW
年份:
2016
代理人:
摘要：
The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of intracellular target proteins. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of the targeted protein’s activity. In some embodiments, the compounds of the invention “re-program” the binding of the presenter proteins to protein targets that either do not normally bind to the presenter protein (e.g., do not show detectable binding in mammalian cells absent the compound). In some embodiments, provided compounds “re-program” presenter protein binding to greatly enhance interaction with a particular target with which it may have some interaction absent the compound. Interactions achieved through such reprogramming result in an ability to modulate the activity of these new targets.本發明提供例如經由結合至呈遞蛋白(例如FKBP家族之成員、親環素家族之成員或PIN1)及靶蛋白(例如真核靶蛋白,如哺乳動物靶蛋白或真菌靶蛋白,或原核靶蛋白,如細菌靶蛋白)而能夠調節生物過程之化合物(例如巨環化合物)。此等化合物結合內源性細胞內呈遞蛋白,諸如FKBP或親環素,且所得二元複合物選擇性地結合細胞內靶蛋白且調節其活性。在所述呈遞蛋白、所述化合物及所述靶蛋白之間三聯複合物的形成係藉由蛋白質-化合物相互作用及蛋白質-蛋白質相互作用兩者驅動,且兩者均為調節靶向蛋白之活性所需的。在一些實施例中,本發明化合物對所述呈遞蛋白與通常不結合至所述呈遞蛋白(例如在不存在所述化合物之情況下在哺乳動物細胞中不顯示可偵測結合)之蛋白標靶之結合「再程式化」。在一些實施例中,提供之化合物對呈遞蛋白結合「再程式化」以極大地增強與特定標靶之相互作用,所述呈遞蛋白與所述特定標靶可在不存在所述化合物之情況下具有某種相互作用。經由此類再程式化實現之相互作用產生調節此等新穎標靶之活性的能力。
