JQAD1

JQAD1 is a CRBN-dependent PROTAC that selectively targets EP300 for degradation. JQAD1 suppresses EP300 expression and the H3K27ac modification. JQAD1 induces apoptosis. JQAD1 can be used in research of cancer[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Epigenetics >> PARP

Signaling Pathways >> Apoptosis >> Caspase

Signaling Pathways >> PROTAC >> PROTAC

Signaling Pathways >> Epigenetics >> Histone Acetyltransferase

Signaling Pathways >> Cell Cycle/DNA Damage >> PARP

JQAD1在对照组 Kelly NB 细胞而不是 CRBN 敲除细胞中抑制 EP300 的表达，抑制 H3K27ac 修饰，并诱导凋亡[1]。 JQAD1 (0.5 or 1 μM; 6-96 h) 处理导致早期时间依赖性诱导亚 G1 峰，表明 Kelly 和 NGP细胞凋亡死亡[1]。 JQAD1 (1 μM; 12-36 h) 诱导 Kelly NB 细胞凋亡[1]。 JQAD1 (0.5 μM; 24 h) 处理的细胞表现出促凋亡的 BH3 效应物 BIM、BID 和 PUMA 以及促凋亡介质 BAX 及其抑制剂 BCL2 和 MCL1 的上调[1]。 JQAD1 (0.5 and 1 μM; 24 h) 破坏 MYCN 表达[1]。 JQAD1 (0.5 μM; 24 h) 导致染色质上 H3K27ac 缺失[1]。 JQAD1 (1.2 nM-20 μM; 5 days) 具有广泛的 CRBN 依赖的跨癌细胞系抗肿瘤活性[1]。 JQAD1 以时间依赖的方式诱导 EP300 降解，最早在 16 小时[1]。 Western Blot Analysis[1] Cell Line: MYCN-amplified NB cells Concentration: 0.1, 0.5, 1, 3, 5, and 10 µM Incubation Time: 24 h Result: Demonstrated a dose-dependent decrease in EP300 expression along with a parallel loss of the H3K27ac modification. Induced selective loss of EP300 expression coincident with cleavage of PARP1, signaling the onset of apoptosis. Western Blot Analysis[1] Cell Line: Kelly NB cells Concentration: 1 µM Incubation Time: 12, 24, and 36 hours Result: Increased the expression of cleaved caspase-3 and cleaved PARP1 in a dose-dependent manner.

JQAD1 (40 mg/kg; i.p.; 每日一次, 持续 21 天) 抑制 Kelly NB 细胞异种移植的 NSG 小鼠的肿瘤生长[1]。 Animal Model: NSG mice with Kelly NB cell xenografts[1] Dosage: 40 mg/kg Administration: Intraperitoneal injection; daily, for 21 days Result: Suppressed tumor growth and prolonged survival. Animal Model: CD1 mice[1] Dosage: 10 mg/kg Administration: Intraperitoneal injection (Pharmacokinetic Analysis) Result: Had a half-life of 13.3 (±3.37 SD) hours in murine serum, with a Cmax of 7 μmol/L.

[1]. Durbin AD, et, al. EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma. Cancer Discov. 2022 Mar 1;12(3):730-751.