INY-03-041 trihydrochloride 是一种有效的、高选择性的、基于 PROTAC 的泛-Akt 降解剂，由ATP 竞争性 Akt 抑制剂Ipatasertib 结合 Lenalidomide 组成。INY-03-041 trihydrochloride 可抑制 AKT1，AKT2 和 AKT3，IC50 分别为 2.0 nM，6.8 nM 和 3.5 nM。
INY-03-041 trihydrochloride is a potent, highly selective and PROTAC-based pan-Akt degrader consisting of the ATP-competitive Akt inhibitor Ipatasertib conjugated to Lenalidomide . INY-03-041 trihydrochloride inhibits AKT1, AKT2 and AKT3 with IC50s of 2.0, 6.8 and 3.5 nM, respectively[1].
INY-03-041 (10-1000 nM; 0-24 hours) induces potent degradation of all three AKT isoforms in MDA-MB-468 cells[1].
INY-03-041 exhibits potent in vitro inhibition of S6K1 (IC50 =37.3 nM) and PKG1 (IC50 = 33.2 nM)[1].
INY-03-041 displays enhanced anti-proliferative effects compared with Ipatasertib in MDA-MB-468 and HCC1937 cells[1].
INY-03-041 (250 nM, 12 h) promotes sustained AKT degradation and inhibition of downstream signaling effects for up to 96 h, even after compound washout[1].
Western Blot Analysis[1]
| Cell Line: | MDA-MB-468 cells |
| Concentration: | 0, 10, 50, 100, 250, 500, and 1000 nM |
| Incubation Time: | 0, 2, 4, 6, 8. 10, 12, and 24 h |
| Result: | Induced potent degradation of all three AKT isoforms in a dose-dependent manner after a 12-h treatment, with maximal degradation observed between 100 and 250 nM. At concentrations of 500 nM and greater, AKT degradation is diminished. Treatment with 250 nM of INY-03-041 over time reveals partial degradation of all AKT isoforms within 4 h and progressive loss of AKT abundance out to 24 h. |
[1]. You I, et al. Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling. Cell Chem Biol. 2020 Jan 16;27(1):66-73.e7.
[2]. Maira SM, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012 Feb;11(2):317-28.
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