Synonym
RBN012759; RBN-012759; RBN 012759;
IUPAC/Chemical Name
7-(cyclopropylmethoxy)-5-fluoro-2-((((1r,4r)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one
InChi Key
NKZDEFKPZSLQRF-MQMHXKEQSA-N
InChi Code
InChI=1S/C19H23FN2O3S/c20-15-7-13(25-9-11-1-2-11)8-16-18(15)19(24)22-17(21-16)10-26-14-5-3-12(23)4-6-14/h7-8,11-12,14,23H,1-6,9-10H2,(H,21,22,24)/t12-,14-
SMILES Code
O=C1NC(CS[C@H]2CC[C@H](O)CC2)=NC3=C1C(F)=CC(OCC4CC4)=C3
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
To be determined
Shelf Life
>2 years if stored properly
Drug Formulation
To be determined
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
PARP14 has been implicated by genetic knockout studies to promote protumor macrophage polarization and suppress the antitumor inflammatory response due to its role in modulating interleukin-4 (IL-4) and interferon-γ signaling pathways.
Biological target:
RBN012759 is a selective inhibitor of PARP14, with an IC50 of <3 nM. RBN012759 displays 300-fold selectivity over the monoPARPs and 1000-fold selectivity over the polyPARPs.
In vitro activity:
The ability of RBN012759 to inhibit PARP14-specific self-MARylation was evaluated. MARylation was detected by immunoblot using an antibody that binds to both MAR and PAR and a PARP14 antibody in IFN-γ-stimulated primary human macrophages. RBN012759 decreased the MAR/PAR signal corresponding to PARP14-self-MARylation in a concentration-dependent manner, further supporting its activity on endogenous PARP14. To reinforce the specificity of PARP14 autoMARylation, the CFPAC-1 cell line was used due to its high endogenous PARP14 baseline level and response to IFN-γ stimulation by increasing PARP14 and ADP-ribosylation. First, endogenous PARP14 was immunoprecipitated from IFN-γ-stimulated CFPAC-1 cells and probed for MAR/PAR. These data demonstrated that PARP14 auto-MARylation is stimulated by IFN-γ and robustly inhibited by RBN012759. In addition, CFPAC-1 cells were stimulated with IFN-γ to increase PARP14 expression and MARylation and treated with increasing concentrations of RBN012759. RBN012759 decreased the MARylation signal in a concentration-dependent manner, similar to that observed in human macrophages.
Reference: ell Chem Biol. 2021 Aug 19;28(8):1158-1168.e13. https://pubmed.ncbi.nlm.nih.gov/33705687/
In vivo activity:
The ability of RBN012759 to engage PARP14 in vivo was also evaluated. C57BL/6 mice were treated with RBN012759 at 300 and 500 mg/kg BID PO for 7 days, during which it was well tolerated with no significant body weight loss observed. Treatment with RBN012759 led to an increase in PARP14 protein in vivo. The 500 mg/kg treatment group showed increased PARP14 protein, while the 300 mg/kg group did not, correlating with RBN012759 plasma exposures at the 12 h time point in which the mouse PARP14-free IC50 value was increased by 6- and <1-fold, respectively. These data support the use of RBN012759 as an in vivo chemical probe that selectively engages PARP14 in tissue.
Reference: ell Chem Biol. 2021 Aug 19;28(8):1158-1168.e13. https://pubmed.ncbi.nlm.nih.gov/33705687/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
163.0 |
431.06 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
378.46
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. Schenkel LB, Molina JR, Swinger KK, Abo R, Blackwell DJ, Lu AZ, Cheung AE, Church WD, Kunii K, Kuplast-Barr KG, Majer CR, Minissale E, Mo JR, Niepel M, Reik C, Ren Y, Vasbinder MM, Wigle TJ, Richon VM, Keilhack H, Kuntz KW. A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants. Cell Chem Biol. 2021 Aug 19;28(8):1158-1168.e13. doi: 10.1016/j.chembiol.2021.02.010. Epub 2021 Mar 10. PMID: 33705687.
In vitro protocol:
1. Schenkel LB, Molina JR, Swinger KK, Abo R, Blackwell DJ, Lu AZ, Cheung AE, Church WD, Kunii K, Kuplast-Barr KG, Majer CR, Minissale E, Mo JR, Niepel M, Reik C, Ren Y, Vasbinder MM, Wigle TJ, Richon VM, Keilhack H, Kuntz KW. A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants. Cell Chem Biol. 2021 Aug 19;28(8):1158-1168.e13. doi: 10.1016/j.chembiol.2021.02.010. Epub 2021 Mar 10. PMID: 33705687.
In vivo protocol:
1. Schenkel LB, Molina JR, Swinger KK, Abo R, Blackwell DJ, Lu AZ, Cheung AE, Church WD, Kunii K, Kuplast-Barr KG, Majer CR, Minissale E, Mo JR, Niepel M, Reik C, Ren Y, Vasbinder MM, Wigle TJ, Richon VM, Keilhack H, Kuntz KW. A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants. Cell Chem Biol. 2021 Aug 19;28(8):1158-1168.e13. doi: 10.1016/j.chembiol.2021.02.010. Epub 2021 Mar 10. PMID: 33705687.
Schenkel LB, Molina JR, Swinger KK, Abo R, Blackwell DJ, Lu AZ, Cheung AE, Church WD, Kunii K, Kuplast-Barr KG, Majer CR, Minissale E, Mo JR, Niepel M, Reik C, Ren Y, Vasbinder MM, Wigle TJ, Richon VM, Keilhack H, Kuntz KW. A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants. Cell Chem Biol. 2021 Aug 19;28(8):1158-1168.e13. doi: 10.1016/j.chembiol.2021.02.010. Epub 2021 Mar 10. PMID: 33705687.
