WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H206475
CAS#: 1434048-34-6 (free base)
Description: Fenebrutinib, also known as GDC-0853, is orally available inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, GDC-0853 inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways, which leads to the inhibition of the growth of malignant B-cells that overexpress BTK. BTK, a member of the Src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival.
Hodoodo Cat#: H206475
Name: Fenebrutinib free base
CAS#: 1434048-34-6 (free base)
Chemical Formula: C37H44N8O4
Exact Mass: 664.35
Molecular Weight: 664.811
Elemental Analysis: C, 66.85; H, 6.67; N, 16.86; O, 9.63
Related CAS #: 1434048-34-6 (free base) 2128304-54-9 (HCl) 2128304-53-8 (mesylate) 2128304-55-0 (sulfate)
Synonym: GDC-0853; GDC 0853; GDC0853; RG-7845; RG7845; RG 7845; Fenebrutinib; Fenebrutinib free base;
IUPAC/Chemical Name: (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one
InChi Key: WNEODWDFDXWOLU-QHCPKHFHSA-N
InChi Code: InChI=1S/C37H44N8O4/c1-23-18-42(27-21-49-22-27)9-10-43(23)26-5-6-33(39-17-26)40-30-13-25(19-41(4)35(30)47)28-7-8-38-34(29(28)20-46)45-12-11-44-31(36(45)48)14-24-15-37(2,3)16-32(24)44/h5-8,13-14,17,19,23,27,46H,9-12,15-16,18,20-22H2,1-4H3,(H,39,40)/t23-/m0/s1
SMILES Code: O=C1C(N2CCN1C3=NC=CC(C(C=C4NC5=NC=C(N6[C@@H](C)CN(C7COC7)CC6)C=C5)=CN(C)C4=O)=C3CO)=CC8=C2CC(C)(C)C8
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
More Info: Note: Structure was from https://newdrugapprovals.org/2016/03/ ( visited on 4/7/2016)
Biological target: | Fenebrutinib (GDC-0853) is a bruton's tyrosine kinase (Btk) inhibitor with Kis of 0.91 nM, 1.6, 1.3, 12.6, and 3.4 nM for WT Btk, and the C481S, C481R, T474I, T474M mutants. |
In vitro activity: | In isolated primary human B cells, GDC-0853 potently inhibited anti-IgM-induced Btk Y223 tyrosine phosphorylation (IC50 = 3.1 nM) and anti-IgM and CD40L-induced B-cell proliferation (IC50 = 1.2 nM and 1.4 nM, respectively) (Table 8). Btk inhibition by GDC-0853 prevented FcγRIII-triggered TNFα production in human monocytes (IC50 = 1.3 nM). In human blood, GDC-0853 potently inhibited up-regulation of the early activation marker CD69 on B cells after overnight anti-IgM stimulation (IC50 = 8 nM). Furthermore, GDC-0853 also suppressed anti-IgM induced Btk Y223 autophosphorylation in human whole blood (IC50 = 11 nM). Taken together, these data demonstrate that GDC-0853 is a highly selective Btk inhibitor that blocks both B-cell BCR and monocyte FcγR signaling. Reference: J Med Chem. 2018 Mar 22;61(6):2227-2245. https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01712 |
In vivo activity: | To evaluate the in vivo efficacy of GDC-0853, it was tested in a B and myeloid cell-dependent inflammatory arthritis model. Female Lewis rats with developing collagen-induced arthritis were dosed orally for 16 days with GDC-0853 at a range of doses once (0.06, 0.25, 1, 4, and 16 mg/kg QD) (Figure 8A) or twice (0.125, 0.5, and 2 mg/kg BID) daily (Figure 8B). GDC-0853 dose-dependently reduced ankle thickness following QD (Figure 8A) and BID (Figure 8B) dosing regimens. Furthermore, GDC-0853 showed a dose responsive beneficial effect on a panel of ankle histopathology parameters (inflammation, pannus, cartilage damage, bone resorption; data not shown). Reference: J Med Chem. 2018 Mar 22;61(6):2227-2245. https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01712 |
Solvent | Max Conc. mg/mL | Max Conc. mM | |
---|---|---|---|
Solubility | |||
DMF | 20.0 | 30.08 | |
DMSO | 17.0 | 25.57 | |
DMSO:PBS (pH 7.2) (1:2) | 0.3 | 0.50 | |
Ethanol | 5.0 | 7.52 |
The following data is based on the product molecular weight 664.81 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. Jones NS, Yoshida K, Salphati L, Kenny JR, Durk MR, Chinn LW. Complex DDI by Fenebrutinib and the Use of Transporter Endogenous Biomarkers to Elucidate the Mechanism of DDI. Clin Pharmacol Ther. 2020 Jan;107(1):269-277. doi: 10.1002/cpt.1599. Epub 2019 Sep 16. PMID: 31376152; PMCID: PMC6977399. 2. Crawford JJ, Johnson AR, Misner DL, Belmont LD, Castanedo G, Choy R, Coraggio M, Dong L, Eigenbrot C, Erickson R, Ghilardi N, Hau J, Katewa A, Kohli PB, Lee W, Lubach JW, McKenzie BS, Ortwine DF, Schutt L, Tay S, Wei B, Reif K, Liu L, Wong H, Young WB. Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development. J Med Chem. 2018 Mar 22;61(6):2227-2245. doi: 10.1021/acs.jmedchem.7b01712. Epub 2018 Feb 23. PMID: 29457982. 3. Crawford JJ, Johnson AR, Misner DL, Belmont LD, Castanedo G, Choy R, Coraggio M, Dong L, Eigenbrot C, Erickson R, Ghilardi N, Hau J, Katewa A, Kohli PB, Lee W, Lubach JW, McKenzie BS, Ortwine DF, Schutt L, Tay S, Wei B, Reif K, Liu L, Wong H, Young WB. Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development. J Med Chem. 2018 Mar 22;61(6):2227-2245. doi: 10.1021/acs.jmedchem.7b01712. Epub 2018 Feb 23. PMID: 29457982. |
In vitro protocol: | 1. Jones NS, Yoshida K, Salphati L, Kenny JR, Durk MR, Chinn LW. Complex DDI by Fenebrutinib and the Use of Transporter Endogenous Biomarkers to Elucidate the Mechanism of DDI. Clin Pharmacol Ther. 2020 Jan;107(1):269-277. doi: 10.1002/cpt.1599. Epub 2019 Sep 16. PMID: 31376152; PMCID: PMC6977399. 2. Crawford JJ, Johnson AR, Misner DL, Belmont LD, Castanedo G, Choy R, Coraggio M, Dong L, Eigenbrot C, Erickson R, Ghilardi N, Hau J, Katewa A, Kohli PB, Lee W, Lubach JW, McKenzie BS, Ortwine DF, Schutt L, Tay S, Wei B, Reif K, Liu L, Wong H, Young WB. Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development. J Med Chem. 2018 Mar 22;61(6):2227-2245. doi: 10.1021/acs.jmedchem.7b01712. Epub 2018 Feb 23. PMID: 29457982. |
In vivo protocol: | 1. Crawford JJ, Johnson AR, Misner DL, Belmont LD, Castanedo G, Choy R, Coraggio M, Dong L, Eigenbrot C, Erickson R, Ghilardi N, Hau J, Katewa A, Kohli PB, Lee W, Lubach JW, McKenzie BS, Ortwine DF, Schutt L, Tay S, Wei B, Reif K, Liu L, Wong H, Young WB. Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development. J Med Chem. 2018 Mar 22;61(6):2227-2245. doi: 10.1021/acs.jmedchem.7b01712. Epub 2018 Feb 23. PMID: 29457982. |
Heteroarylpyridone and azapyridone compounds as inhibitors of BTK activity and their preparation
By Crawford, James John; Ortwine, Daniel Fred; Wei, Binqing; Young, Wendy B.
From PCT Int. Appl. (2013), WO 2013067274 A1 20130510.