RBN012759
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MedKoo CAT#: 207164

CAS#: 2360851-29-0

Description: RBN012759 is a potent and selective PARP14 inhibitor which decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants. RBN012759 inhibits PARP14 with a biochemical half-maximal inhibitory concentration of 0.003 μM, exhibits >300-fold selectivity over all PARP family members, and its profile enables further study of PARP14 biology and disease association both in vitro and in vivo. Inhibition of PARP14 with RBN012759 reverses IL-4-driven protumor gene expression in macrophages and induces an inflammatory mRNA signature similar to that induced by immune checkpoint inhibitor therapy in primary human tumor explants.


Chemical Structure

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RBN012759
CAS# 2360851-29-0

Theoretical Analysis

MedKoo Cat#: 207164
Name: RBN012759
CAS#: 2360851-29-0
Chemical Formula: C19H23FN2O3S
Exact Mass: 378.1413
Molecular Weight: 378.4624
Elemental Analysis: C, 60.30; H, 6.13; F, 5.02; N, 7.40; O, 12.68; S, 8.47

Price and Availability

Size Price Availability Quantity
25.0mg USD 1250.0 2 Weeks
50.0mg USD 2250.0 2 Weeks
100.0mg USD 3650.0 2 Weeks
200.0mg USD 4950.0 2 Weeks
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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

Appearance: 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: 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

Product Data:

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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 163.0 431.06

Preparing Stock Solutions

The following data is based on the product molecular weight 378.4624 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.

Recalculate based on batch purity %
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.

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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.

RBN012759

25.0mg / USD 1250.0


Additional Information

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.