CB5083

• CAT Number: I001945
• CAS Number: 1542705-92-9
• Molecular Formula: C₂₄H₂₃N₅O₂
• Molecular Weight: 413.47
• Purity: ≥95%
• Synonyms: 1-[7,8-dihydro-4-[(phenylmethyl)amino]-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide
• Target: p97
• Solubility: 10 mM in DMSO
• Storage: -20°C
• IC50: 11 nM
• InChI: 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)
• InChIKey: RDALZZCKQFLGJP-UHFFFAOYSA-N
• SMILES: CC1=CC2=C(C=CC=C2N1C3=NC4=C(COCC4)C(=N3)NCC5=CC=CC=C5)C(=O)N

CB-5083 is a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor with IC50 of 11nM.IC50 value: 11 nMTarget: p97in vitro: CB-5083 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell death.in vivo: In tumor bearing mice, oral administration of CB-5083 causes rapid accumulation of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to sustained antitumor activity in in vivo xenograft models of both solid and hematological tumors. CB-5083 has good metabolic stability with a 102 min T1/2 in a mouse liver microsomal stability study and a 172 min T1/2 in a hepatocyte stability study. CB-5083 also has excellent permeability as assessed in a Caco-2 assay. PK studies revealed that CB-5083 has moderate absolute oral bioavailability (41%) in mouse, making it suitable for preclinical development.

Reference

1:J Med Chem. 2015 Dec 24;58(24):9480-97. doi: 10.1021/acs.jmedchem.5b01346. Epub 2015 Dec 4. Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083).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, PMID: 26565666 DOI: 10.1021/acs.jmedchem.5b01346 Abstract: The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin-proteasome system (UPS) mediated protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell death. In tumor bearing mice, oral administration of 71 causes rapid accumulation of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to sustained antitumor activity in in vivo xenograft models of both solid and hematological tumors. 71 has been taken into phase 1 clinical trials in patients with multiple myeloma and solid tumors.