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CCT020312 Sale

目录号 : GC33006

An EIF2AK3 activator

CCT020312 Chemical Structure

Cas No.:324759-76-4

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10mM (in 1mL DMSO)
¥1,916.00
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5mg
¥1,607.00
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10mg
¥2,767.00
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50mg
¥8,550.00
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100mg
¥14,498.00
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产品描述

CCT020312 is an activator of eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3).1 It increases phosphorylation of eIF2α at serine 51 in HT-29 colon carcinoma and MCF-7 breast cancer cells when used at a concentration of 10 ?M, an effect not seen in cells transfected with EIF2AK3 siRNA. It reduces phosphorylation of the tumor suppressor retinoblastoma (Rb) protein in HT-29 cells (EC50 = 5.1 ?M). CCT020312 (10 ?M) rapidly reduces the level of cyclin D1 in HT-29 cells. It also inhibits the growth of HT-29 cells (GI50 = 2.1 ?M).

1.Stockwell, S.R., Platt, G., Barrie, S.E., et al.Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signallingPLoS One7(1)e28568(2012)

Chemical Properties

Cas No. 324759-76-4 SDF
Canonical SMILES O=C1NC2=C(C(C3=CC=CC=C3)=C1C4=NN(C(C4)C5=CC=C(C=C5)Br)C(CCN(CC)CC)=O)C=C(C=C2)Br
分子式 C31H30Br2N4O2 分子量 650.4
溶解度 DMSO : 125 mg/mL (192.19 mM);Water : < 0.1 mg/mL (insoluble) 储存条件 Store at -20°C
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1 mM 1.5375 mL 7.6876 mL 15.3752 mL
5 mM 0.3075 mL 1.5375 mL 3.075 mL
10 mM 0.1538 mL 0.7688 mL 1.5375 mL
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Research Update

CCT020312 Inhibits Triple-Negative Breast Cancer Through PERK Pathway-Mediated G1 Phase Cell Cycle Arrest and Apoptosis

Front Pharmacol 2020 May 19;11:737.PMID:32508655DOI:10.3389/fphar.2020.00737.

Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific therapeutic targets. CCT020312, a selective eukaryotic translation initiation factor 2 alpha (eIF2α)/protein kinase RNA-like endoplasmic reticulum kinase (PERK) activator, may have a potent anti-tumor effect. In the present study, we examined the effects of CCT020312 on TNBC and explored the underlying mechanism. We found that CCT020312 inhibited the viability of TNBC cell lines, MDA-MB-453 and CAL-148, by inducing apoptosis and G1 phase cell cycle arrest. CCT020312 decreased the protein levels of cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, and B-cell lymphoma 2 (Bcl-2) and increased the levels of Bcl-2-associated X protein (Bax) and cleaved poly (ADP-ribose) polymerase (PARP) compared with those in the control. CCT020312 activated PERK/eIF2α/activating transcription factor 4 (ATF4)/CCAAT-enhancer binding protein (C/EBP) homologous protein transcription factor (CHOP) signaling and inhibited protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Furthermore, CCT020312 inhibited tumor growth in an MDA-MB-453 orthotopic xenograft mouse model by activating the PERK/eIF2α/ATF4/CHOP pathway and inhibiting the AKT/mTOR pathway. Thus, our study shows that CCT020312 may be a potential drug candidate for TNBC treatment.

PERK controls bone homeostasis through the regulation of osteoclast differentiation and function

Cell Death Dis 2020 Oct 13;11(10):847.PMID:33051453DOI:10.1038/s41419-020-03046-z.

Osteoclasts are multinucleated giant cells with the ability to degrade bone tissue, and are closely related to abnormal bone metabolic diseases. Endoplasmic reticulum (ER) is an organelle responsible for protein modification, quality control, and transportation. The accumulation of unfolded or misfolded proteins in ER cavity induces ER stress. Double-stranded RNA-dependent protein kinase-like ER kinase (PERK) is an ER stress-sensing protein, which is ubiquitous in eukaryotic cells. Systemic PERK knockout mice show severe bone loss, suggesting that PERK is of great significance for maintaining the normal growth and development of bone tissue, but the role of PERK in osteoclastogenesis is still unclear. In this study, we found that PERK was significantly activated during RANKL-induced osteoclast differentiation; knockdown of PERK by siRNA and inhibition of PERK by GSK2606414, respectively, had significant negative regulatory effects on the formation and bone resorption of osteoclasts. PERK inhibitor GSK2606414 down-regulated the mRNA levels and protein expression of osteoclast differentiation marker genes, and inhibited RANKL-induced activation of Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Treatment with PERK inhibitor GSK2606414 in ovariectomized mouse model significantly suppressed bone loss and osteoclast formation. Thapsigargin activated ER stress to enhance autophagy, while GSK2606414 had a significant inhibitory effect on autophagy flux and autophagosome formation. Antioxidant N-acetylcysteine (NAC) could inhibit the expression of PERK phosphorylation, osteoclast-related proteins and autophagy-related proteins, but the use of PERK activator CCT020312 can reverse inhibition effect of NAC. Our findings demonstrate a key role for PERK in osteoclast differentiation and suggest its therapeutic potential.

PERK activator CCT020312 prevents inflammation-mediated osteoporosis in the ovariectomized rats

Gynecol Endocrinol 2021 Apr;37(4):342-348.PMID:33480297DOI:10.1080/09513590.2021.1874904.

Objective: To investigate the therapeutic effects of PERK activator CCT020312 (CCT) on inflammation-mediated osteoporosis (IMO) in ovariectomized rats. Methods: Rats were divided into Sham, IMO, IMO + 1 mg/kg CCT and IMO + 2 mg/kg CCT groups. IMO models were constructed by bilateral ovariectomy (OVX) on 1st day followed by injection with magnesium silicate (Talc) on the 59th day. Sham rats did not undergo OVX surgery and were injected with saline instead of Talc. From 60th to 79th day, rats were treated with DMSO (vehicle control) in the Sham and IMO groups, and 1 or 2 mg/kg CCT020312 in treatment groups. Osteopontin (OPN), osteocalcin (OCN), tartrate-resistant acid phosphatase (TRAP), C-terminal telopeptide of type I collagen (CTX-I), and pro-inflammatory factors were measured on the 80th day. ProdigyDEXA was used to evaluate bone mineral density and content (BMD/BMC). Bone volume/total volume (BV/TV), connectivity density (Conn.D), trabecular number (Tb.N), and trabecular separation (Tb.Sp) was assessed using 3D micro-CT scanner. Results: CCT up-regulated Conn.D, BV/TV, and Tb.N, but down-regulated Tb.Sp in IMO rats. Besides, the declined femoral BMD and BMC in IMO rats were elevated after CCT treatment. Besides, IMO rats represented declined OPN and OCN, as well as increased TRAP, CTX-I, and pro-inflammatory factors, whereas those in the treatment groups were ameliorated regarding these indexes, with 2 mg/kg CCT showing better effect. Conclusion: PERK activator CCT020312 can be served as a new therapeutic option for the protection against bone loss in the OVX rat model associated with inflammation probably by manipulating inflammatory factors.

PERK activation by CCT020312 chemosensitizes colorectal cancer through inducing apoptosis regulated by ER stress

Biochem Biophys Res Commun 2021 Jun 11;557:316-322.PMID:33894420DOI:10.1016/j.bbrc.2021.03.041.

Endoplasmic reticulum (ER) stress is a significant mechanism for chemoresistance to colorectal cancer (CRC) treatment. The RNA-like endoplasmic reticulum kinase (PERK) is critical for ER stress induction. In the present study, we attempted to explore whether PERK activator CCT020312 (CCT) could be effective for CRC treatment, and reveal the underlying mechanisms. We first found that CCT dose- and time-dependently reduced CRC cell proliferation. Importantly, it markedly improved the chemosensitivity of CRC cells that were drug-sensitive or -resistant to taxol treatment, as evidenced by the significantly decreased cell viability. Moreover, CCT at the non-toxic concentration exhibited obviously synergistic effects with taxol to induce apoptosis and cell cycle arrest in G2/M phase in vitro. In addition, we showed that CCT alone considerably induced ER stress in CRC cells through a dose- and time-dependent fashion. Meanwhile, CCT combined with taxol caused significant ER stress through improving phosphorylated PERK, eukaryotic translation initiation factor 2α (eIF2ɑ), C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78). More studies showed that the interaction between PERK and GRP78 was a potential target for CCT to perform its regulatory events. Intriguingly, PERK knockdown markedly abolished the regulatory role of CCT and taxol cotreatments in cell proliferation suppression and apoptosis induction, indicating the importance of PERK for CCT to perform its anti-cancer bioactivity. Our in vivo experiments confirmed that CCT plus taxol dramatically reduced tumor growth in CRC xenografts. Together, all these results suggested that promoting PERK activation by CCT may be an effective therapeutic strategy to improve CRC to taxol treatment.

Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling

PLoS One 2012;7(1):e28568.PMID:22253692DOI:10.1371/journal.pone.0028568.

Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for pathway selective agent development. We demonstrate that consistent with its mode of action CCT020312 is capable of delivering potent, and EIF2AK3 selective, proliferation control and can act as a sensitizer to chemotherapy-associated stresses as elicited by taxanes.