OARV-771

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Size

Price

Stock

Quantity

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In stock

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

Canonical 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

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