WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 206489
Description: CB-5083 is a novel first in class, potent orally bio-available p97 inhibitor that disrupts cellular protein homeostasis and demonstrates anti-tumor activity in solid and hematological models . CB-5083 causes rapid and sustained accumulation of poly-ubiquitin in tumor xenografts after a single administration. CB-5083 showed activity to inhibit tumor growth in multiple rodent models of human cancer. Furthermore, CB-5083 appears to exhibit greater potency over current proteasome inhibitors that further validate targeting p97 and protein homeostasis in the treatment of cancer.
MedKoo Cat#: 206489
Chemical Formula: C24H23N5O2
Exact Mass: 413.18518
Molecular Weight: 413.4
Elemental Analysis: C, 69.72; H, 5.61; N, 16.94; O, 7.74
Synonym: CB5083; CB-5083; CB 5083.
IUPAC/Chemical Name: 1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide
InChi Key: RDALZZCKQFLGJP-UHFFFAOYSA-N
InChi Code: InChI=1S/C24H23N5O2/c1-15-12-18-17(22(25)30)8-5-9-21(18)29(15)24-27-20-10-11-31-14-19(20)23(28-24)26-13-16-6-3-2-4-7-16/h2-9,12H,10-11,13-14H2,1H3,(H2,25,30)(H,26,27,28)
SMILES Code: O=C(C1=CC=CC2=C1C=C(C)N2C3=NC(NCC4=CC=CC=C4)=C(COCC5)C5=N3)N.
Appearance: White to off-white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||CB-5083 selectively inhibits p97 through its D2 site with the IC50 of 11 nM.|
|In vitro activity:||p97 inhibition with small molecules has been shown to induce endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) (5, 19). CB-5083 caused a strong induction of the UPR as measured by the phosphorylation of PERK and accumulation of sXBP1 and BiP (Fig. 2A; Supplementary Fig. S2). CB-5083 treatment led to a robust induction of the transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). K48-linked polyubiquitin accumulation, a hallmark of inhibition of protein degradation (20, 21), was followed as a pathway marker for p97 inhibition (Fig. 2A and B). CB-5083, like bortezomib, induced a rapid accumulation of K48-linked polyubiquitinated proteins in cultured cells. The UPR was activated, and CHOP protein expression increased up to 2.7-fold compared with baseline levels. Consequently, apoptosis was activated, as demonstrated by an increase in cleaved PARP (cPARP) levels (Fig. 2C). Reference: Mol Cancer Ther. 2017 Nov;16(11):2375-2386. https://mct.aacrjournals.org/content/16/11/2375.long|
|In vivo activity:||The P97 inhibitor CB-5083 can inhibit osteosarcoma cell proliferation and effectively induce apoptosis. The in vivo antitumor ability of the P97 inhibitor CB-5083 was investigated using a nude mouse xenograft model established with SJSA-1 cells. Once the tumor volume reached approximately 100 mm3, the mice were randomly divided into two groups (vehicle group and CB-5083 group): the CB-5083 group was treated with 100 mg/kg CB-5083 every day, whereas the vehicle group was treated with normal saline (with the same volume of DMSO). The P97 inhibitor CB-5083 inhibited tumor growth beginning 15 days after the first injection, and significant inhibition was detected through the end of the study (Figure 3A). The average tumor weight of the vehicle group was 823 mg, whereas that of the CB-5083 group was 416 mg, which also indicated an in vivo reduction in osteosarcoma growth (Figure 3B). The average body weights of the nude mice in the different groups showed no significant changes, which indicated that CB-5083 exhibits low toxicity (Figure 3C). These results demonstrated that the P97 inhibitor CB-5083 exhibits prominent antitumor properties and no distinct toxicity in vivo. Reference: Am J Transl Res. 2020 Jun 15;12(6):2956-2967. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344079/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 413.4 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|Formulation protocol:||1. Gareau A, Rico C, Boerboom D, Nadeau ME. In vitro efficacy of a first-generation valosin-containing protein inhibitor (CB-5083) against canine lymphoma. Vet Comp Oncol. 2018 Sep;16(3):311-317. doi: 10.1111/vco.12380. Epub 2018 Jan 4. PMID: 29314493. 2. Le Moigne R, Aftab BT, Djakovic S, Dhimolea E, Valle E, Murnane M, King EM, Soriano F, Menon MK, Wu ZY, Wong ST, Lee GJ, Yao B, Wiita AP, Lam C, Rice J, Wang J, Chesi M, Bergsagel PL, Kraus M, Driessen C, Kiss von Soly S, Yakes FM, Wustrow D, Shawver L, Zhou HJ, Martin TG 3rd, Wolf JL, Mitsiades CS, Anderson DJ, Rolfe M. The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma. Mol Cancer Ther. 2017 Nov;16(11):2375-2386. doi: 10.1158/1535-7163.MCT-17-0233. Epub 2017 Sep 6. PMID: 28878026.|
|In vitro protocol:||1. Gareau A, Rico C, Boerboom D, Nadeau ME. In vitro efficacy of a first-generation valosin-containing protein inhibitor (CB-5083) against canine lymphoma. Vet Comp Oncol. 2018 Sep;16(3):311-317. doi: 10.1111/vco.12380. Epub 2018 Jan 4. PMID: 29314493.|
|In vivo protocol:||1. Le Moigne R, Aftab BT, Djakovic S, Dhimolea E, Valle E, Murnane M, King EM, Soriano F, Menon MK, Wu ZY, Wong ST, Lee GJ, Yao B, Wiita AP, Lam C, Rice J, Wang J, Chesi M, Bergsagel PL, Kraus M, Driessen C, Kiss von Soly S, Yakes FM, Wustrow D, Shawver L, Zhou HJ, Martin TG 3rd, Wolf JL, Mitsiades CS, Anderson DJ, Rolfe M. The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma. Mol Cancer Ther. 2017 Nov;16(11):2375-2386. doi: 10.1158/1535-7163.MCT-17-0233. Epub 2017 Sep 6. PMID: 28878026.|
1: Zhou HJ, Wang J, Yao B, Wong S, Djakovic S, Kumar B, Rice J, Valle E, Soriano F, Menon MK, Madriaga A, Kiss von Soly S, Kumar A, Parlati F, Yakes FM, Shawver L, Le Moigne R, Anderson DJ, Rolfe M, Wustrow D. Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083). J Med Chem. 2015 Dec 24;58(24):9480-97. doi: 10.1021/acs.jmedchem.5b01346. Epub 2015 Dec 4. PubMed PMID: 26565666.
2: Anderson DJ, Le Moigne R, Djakovic S, Kumar B, Rice J, Wong S, Wang J, Yao B, Valle E, Kiss von Soly S, Madriaga A, Soriano F, Menon MK, Wu ZY, Kampmann M, Chen Y, Weissman JS, Aftab BT, Yakes FM, Shawver L, Zhou HJ, Wustrow D, Rolfe M. Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis. Cancer Cell. 2015 Nov 9;28(5):653-65. doi: 10.1016/j.ccell.2015.10.002. PubMed PMID: 26555175.