Name: OARV-771
Brand: BOC Sciences
Rating: 5 (1 reviews)

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IUPACName

2-[3-[2-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-2-oxoethoxy]propoxy]ethyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^2,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate

Synonyms

2-(3-(2-(((S)-1-((2S,4R)-4-Hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)propoxy)ethyl 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate

Density

1.38±0.1 g/cm3

InChI Key

CWTFXHWWWKKEQI-QQRWPDCKSA-N

InChI

InChI=1S/C49H59ClN8O8S2/c1-27-30(4)68-48-41(27)42(33-14-16-35(50)17-15-33)53-37(45-56-55-31(5)58(45)48)23-40(61)66-21-20-64-18-9-19-65-25-39(60)54-44(49(6,7)8)47(63)57-24-36(59)22-38(57)46(62)52-28(2)32-10-12-34(13-11-32)43-29(3)51-26-67-43/h10-17,26,28,36-38,44,59H,9,18-25H2,1-8H3,(H,52,62)(H,54,60)/t28-,36+,37-,38-,44+/m0/s1

SMILES

CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)OCCOCCCOCC(=O)NC(C(=O)N4CC(CC4C(=O)NC(C)C5=CC=C(C=C5)C6=C(N=CS6)C)O)C(C)(C)C)C7=CC=C(C=C7)Cl)C

Mechanism

Target: OARV-771 targets BET bromodomain proteins BRD2, BRD3, and BRD4.

Binding site: Its BET ligand binds acetyl-lysine recognition pockets of BET bromodomains.

Mechanism of action: OARV-771 is a VHL-based BET PROTAC engineered with improved cellular permeability relative to earlier BET degrader scaffolds. The molecule links a BET bromodomain ligand to a von Hippel-Lindau E3 ligase ligand, enabling recruitment of BRD2, BRD3, and BRD4 to VHL-dependent ubiquitination machinery. This proximity-driven mechanism promotes rapid proteasomal degradation of BET proteins and sustained disruption of BET-regulated transcriptional programs. OARV-771 is useful for studying chromatin reader dependency, BET paralog degradation potency, cell-permeability effects on degrader performance, and degradation-mediated suppression of oncogenic transcriptional networks.

Applications

• PROTAC-Mediated Oncogene Degradation: OARV-771 is utilized in research to selectively degrade oncogenic proteins implicated in cancer progression. By harnessing the ubiquitin-proteasome system, this PROTAC facilitates the targeted removal of disease-causing proteins, offering a powerful tool for studying cancer biology and potential therapeutic interventions.

• Targeted Kinase Degradation: Researchers employ OARV-771 to achieve the specific degradation of kinase proteins involved in aberrant signaling pathways. This application enables the elucidation of kinase function and regulation, providing insights into the development of novel therapeutic strategies for diseases driven by kinase dysregulation.

• Protein-Protein Interaction Modulation: OARV-771 aids in the study of protein-protein interactions by promoting the degradation of key proteins within these complexes. This approach allows scientists to dissect interaction networks and understand their roles in cellular processes, advancing the field of targeted protein degradation research.

• Neurodegenerative Disease Research: By facilitating the degradation of proteins associated with neurodegenerative disorders, OARV-771 serves as a valuable tool for exploring the pathogenesis of these diseases. Researchers can investigate the impact of protein clearance on cellular health, contributing to the development of innovative therapeutic approaches.

1. Amide-to-ester substitution as a strategy for optimizing PROTAC permeability and cellular activity.

Klein, V.G., Bond, A.G., Craigon, C., Lokey, R.S. and Ciulli, A., 2021. Journal of medicinal chemistry, 64(24), pp.18082-18101.

Criteria for predicting the druglike properties of "beyond Rule of 5" Proteolysis Targeting Chimeras (PROTAC) degraders are underdeveloped. PROTAC components are often combined via amide couplings due to their reliability. Amides, however, can give rise to poor absorption, distribution, metabolism, and excretion (ADME) properties. We hypothesized that a bioisosteric amide-to-ester substitution could lead to improvements in both physicochemical properties and bioactivity. Using model compounds, bearing either amides or esters, we identify parameters for optimal lipophilicity and permeability. We applied these learnings to design a set of novel amide-to-ester-substituted, VHL-based BET degraders with the goal to increase permeability. Our ester PROTACs retained intracellular stability, were overall more potent degraders than their amide counterparts, and showed an earlier onset of the hook effect. These enhancements were driven by greater cell permeability rather than improvements in ternary complex formation. This largely unexplored amide-to-ester substitution provides a simple strategy to enhance PROTAC permeability and bioactivity and may prove beneficial to other beyond Ro5 molecules.

Can it Improved cell permeability?

OARV-771 is designed with improved cell permeability, allowing it to effectively enter cells and reach its target BET proteins. This is crucial for its activity, as traditional BET degraders often struggle to penetrate cell membranes.

21/1/2017

Hi, may I know its Potent and selective? thank you.

OARV-771 exhibits high potency, with DC50 values of 6, 1, and 4 nM for degrading Brd4, Brd2, and Brd3, respectively. This means it requires very low concentrations to achieve significant effects. It also shows good selectivity towards BET proteins over other proteins, minimizing potential side effects.

17/8/2021

I wouldl like to confirm that is it a VHL-based PROTAC?

Unlike traditional BET inhibitors that directly block their function, OARV-771 takes a different approach. It acts as a PROTAC, meaning it recruits the body's own protein degradation machinery, the E3 ubiquitin ligase complex (particularly VHL), to tag and degrade BET proteins. This approach can lead to more sustained and complete protein depletion compared to inhibitors.

14/10/2021

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* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂