| CB-5083p97 inhibitor |
Sample solution is provided at 25 µL, 10mM.
Nature.2017 Jan 19;541(7637):417-420.
Nature.2018 Nov;563(7731):407-411.Nature.2018 Jun 13.Nature.2018 Jun 27.Nature.2018 Mar 29;555(7698):673-677.Nature.2017 Sep 7;549(7670):96-100.Nature.2016 Apr 21;532(7599):398-401.
Science.2016 Aug 5;353(6299)594-8Nat Nanotechnol.2017 Dec;12(12):1190-1198.Nature Biotechnology.2017 Jun;35(6):569-576Nat Med.2018 Sep 17.Cell.2018 Dec 21. pii: S0092-8674(18)31561-7.Cell.Available online 25 October 2018.Cell.2018 Sep 27. pii: S0092-8674(18)31183-8.Cell.2018 Jun 28;174(1):172-186.e21.Cell.2018 Feb 22;172(5):1007-1021.e17.Cell.2017 Nov 30;171(6):1284-1300.e21.Cell.2017 Aug 17. pii: S0092-8674(17)30869-3.Cell.2017 Jul 13;170(2):312-323Nat Med.2018 Jan 29.Nat Med.2017 Nov;23(11):1342-1351.Cell.2017 Apr 6;169(2):286-300.Cell.2015 Aug 27;162(5):987-1002.Cell.2015 Feb 12;160(4):729-44.Nature Medicine.2017 Apr;23(4):493-500.Cancer Cell.2018 May 14;33(5):905-921.e5.Cancer Cell.2018 Apr 9;33(4):752-769.e8.Cancer Cell.2018 Mar 12;33(3):401-416.e8.Cancer Cell.2017 Aug 14;32(2):253-267.e5.Nat Methods.2018 Jul;15(7):523-526.Cell Stem Cell.2018 May 3;22(5):769-778.e4.Cell Stem Cell.2017 Nov 20. pii: S1934-5909(17)30375-2.Quality Control & MSDS
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- Purity = 98.11%
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Chemical structure
| Kinase experiment [1]: | |
Binding assays | CB-5083 IC50 analyses for p97 and mutants were conducted utilizing a standard NADH-based coupled kinetic ATPase assay. The assay was conducted in 384 well plates in 50 μl volume with 60 nM p97 enzyme, 500 μM ATP, 3 units/ml each of pyruvate kinase and lactate-dehydrogenase, 250 μM NADH and 3.75 mM phosphoenolpyruvate. ATP hydrolysis dependent NADH reduction was measured at 340 nM wavelength after 2 hours incubation at 37 °C. ATP competition with CB-5083 was measured in the NADH assay with increasing concentrations of ATP. For the ADP-glo assay, compounds were diluted in DMSO with a three-fold ten-point serial dilution to achieve assay concentrations ranging from 10 μM to 0.16 nM. The assay was performed by incubating 20 nM p97, 20 μM ATP and serial diluted compounds in 5 μl volume at 37 °C for 15 min. ADP glo reagents 1 and 2 were added. The IC50 of each compound was derived by reading luminescence values and fitting the values to a 4 point sigmoidal curve. |
| Cell experiment [1]: | |
Cell lines | HEK293T stably expressing TCRα-GFP, A549 and HCT116 cell lines |
Preparation method | The solubility of this compound in DMSO is >20.7mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
Reacting condition | 2.5 μM, 6 hr; |
Applications | In human embryonic kidney 293T cells stably expressing TCRα-GFP, CB-5083 treatment led to a dose-dependent accumulation of TCRα-GFP in the ER with EC50 of 0.73 ± 0.04 μM. In the lung carcinoma cell line A549, CB-5083 led to accumulation of poly-ubiquitinated proteins. In HCT116 cells, CB-5083 treatment resulted in accumulation of K48-ubiquitinated proteins at a higher molecular weight. |
| Animal experiment [2]: | |
Animal models | Nude or SCID-Beige mice xenografted with HCT116 derived from colorectal adenocarcinoma, NCI-H1838 derived from non-small-cell lung cancer, AMO-1 derived from a plasmacytoma, and colorectal cancer patient-derived xenograft (PDX) models |
Dosage form | oral administration, 25 and 100 mg/kg, 6 hr. oral gavage once (qd) or twice (bid) daily or following a 4 days on, 3 days off (qd4/3off) cycle. |
Application | CB-5083 (oral, 25 and 100 mg/kg) induced the UPR and apoptosis. Oral treatment with CB-5083 inhibited the growth of human tumor xenografts in mice. |
Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
References: [1]. Anderson D J, Le Moigne R, Djakovic S, et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis[J]. Cancer Cell, 2015, 28(5): 653-665. | |
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| Cas No. | 1542705-92-9 | SDF | Download SDF |
| Synonyms | N/A | ||
| Chemical Name | (E)-1-(4-(benzylimino)-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbimidic acid | ||
| Canonical SMILES | CC1=CC2=C(C(O)=N)C=CC=C2N1C3=NC4=C(/C(N3)=NCC5=CC=CC=C5)COCC4 | ||
| Formula | C24H23N5O2 | M.Wt | 413.47 |
| Solubility | ≥20.65mg/mL in DMSO | Storage | Store at -20°C |
| Physical Appearance | A solid | Shipping Condition | Evaluation sample solution : ship with blue ice.All other available size:ship with RT , or blue ice upon request |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. | ||
IC50: 15.4 nM
CB-5083 is an orally bioavailable inhibitor of p97. P97 is an AAA-ATPase involved in multiple cellular functions such as organelle membrane homotypic fusion and sorting of endosomal cargo. P97 is also known as valosin-containing protein which plays important roles in regulating protein homeostasis [1].
In vitro: CB-5083 is a selective potent inhibitor of p97’s second ATPase domain. CB-5083 might compete with ATP for the same binding site but may adopt a different orientation[2]. The IC50 of CB-5083 against wild-type (WT) p97 was 15.4 nM. CB-5083 could dose-dependently increase the cytosolic protein degradation in HEK293T, A549 and HCT116 cell lines [1]. CB-5083 treatment (2.5 μM) of A549 cells for 24h could induce cancer cell death [1].
In vivo: In female nude mice bearing HCT116, A549 lung carcinoma, and AMO-1 multiple myeloma xenograft tumors, oral administration of CB-5083 (100 mg/kg) for 6 h showed a significant antitumor response in tumors (TGI = 63%, p < 0.0001) [1,2].
Clinical trial: CB-5083 has entered phase 1 clinical trials in patients with multiple myeloma and solid tumors.
References:Anderson D J, Le Moigne R, Djakovic S, et al. Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis[J]. Cancer cell, 2015, 28(5): 653-665.Zhou H J, Wang J, Yao B, et al. Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)[J]. Journal of medicinal chemistry, 2015, 58(24): 9480-9497.
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请赐教！
荚膜（capsule）是某些细菌在生长繁殖过程中分泌的一层黏液性物质，包围在细胞壁外，通常这种黏液层厚度小于0.2μm，成分是多糖或多肽，只有在营养丰富时或在动物体内，细菌才产生这种半抗原性质的黏液性物质。它具有保护菌体免受巨噬细胞等的捕捉和吞噬，因而具有抗吞噬抗消化、侵袭力强、与致病性关系密切等特点。像肺炎球菌、炭疽杆菌等都有这类荚膜。有些细菌的荚膜层较薄，小于0.2μm，称为微荚。
像链球菌的M蛋白、伤寒杆菌的Vi抗原、大肠杆菌的K抗原等都属于这类微荚膜。
颗粒型抗原,除了有细菌、红细胞、螺旋体等天然颗粒型抗原,还有吸附有可溶性抗原的非免疫相关颗粒.
颗粒性抗原光镜下可见，比如细菌性抗原、红细胞抗原等；而可溶性抗原在光镜下不可见，如组织浸出液、细菌毒素、蛋白质分子等。
它们不等同于完全抗原和不完全抗原。完全抗原具有免疫原性和抗原性，而不完全抗原只具有抗原性。完全抗原可以是颗粒性抗原，亦可是可溶性抗原，而不完全抗原一般只能是可溶性抗原，不会是颗粒性抗原。
若已进入细胞内。则先由巨噬细胞吞噬降解。并形成抗原-MHC复合体传送到表面。被辅助性T淋巴细胞识别和效应T淋巴细胞识别后。效应T淋巴细胞被激活。分解靶细胞。然后再由效应B细胞分泌的抗体进一步消灭病毒。
还有不清楚的么？
