CCT020312

CCT020312 is capable of delivering potent, and eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3) selective, proliferation control and also is an activator of RNA-like endoplasmic reticulum kinase (PERK).

Signaling Pathways >> Cell Cycle/DNA Damage >> Eukaryotic Initiation Factor (eIF)

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

Research Areas >> Cancer

EIF2AK3[1]. PERK[2].

Treatment of HT29 cells with CCT020312 for 24 hours reveal a concentration-dependent loss of P-S608-pRB signal, with a linear response between 1.8 and 6.1 μM. CCT020312 treatment effectively inhibits cell proliferation (as measured at 96 hours) even if treatment is for 2 hours only with subsequent compound washout, indicating that CCT020312 is capable of eliciting durable rather than transient cytostasis. Treatment of HT29 cells with 10 μM CCT020312 for 24 hours reduce the amount of the G1/S cyclins D1, D2, E and A as well as the CDK catalytic subunit CDK2 and increased the level of the CDK inhibitor p27KIP1 present in such cells[1].

Treatment of mice with the PERK activator CCT020312 leads to increased levels of phosphorylated PERK and NRF2 in brain homogenates[2].

Mice[2] For the short-term target engagement trial with ascending doses, 15-week-old wild-type mice (n=3 per group) are treated on three consecutive days with intraperitoneal (i.p.) injections of either 1, 2, or 5 mg/kg/day of CCT020312. For the long-term target engagement trial, 9-week-old wild-type mice (n=3 per group) are treated i.p. for 6 weeks with either 2 mg/kg/day of CCT020312 or equivalent volumes of saline. For immunoblotting of tau species in mouse brains, 17-week-old P301S tau transgenic mice (n=3) are i.p. injected with 2 mg/kg/day of CCT020312 for 6 weeks. For the efficacy trial on behavioral deficits at the early disease stage, 9-week-old P301S tau transgenic mice (n=8 per group) and wild-type mice (n=9 per group) receive i.p. injections of 2 mg/kg/day CCT020312 or equivalent volumes of saline for 6 weeks[2].

[1]. Stockwell SR, et al.Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. PLoS One. 2012;7(1):e28568.

[2]. Bruch J, et al. PERK activation mitigates tau pathology in vitro and in vivo. EMBO Mol Med. 2017 Mar;9(3):371-384.

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