Name: GSK215
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

Solid Powder

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

IUPACName

(2S,4R)-4-hydroxy-1-[(2S)-2-[[2-[4-[3-methoxy-4-[[4-[2-(methylcarbamoyl)anilino]-5-(trifluoromethyl)pyridin-2-yl]amino]phenyl]piperazin-1-yl]acetyl]amino]-3,3-dimethylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Synonyms

(2S,4R)-4-Hydroxy-1-((S)-2-(2-(4-(3-methoxy-4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Boiling Point

1103.2±65.0°C at 760 mmHg

Density

1.317±0.06 g/cm3

InChI Key

ZGSWGXNEXAXEGV-XFCHVEHOSA-N

InChI

InChI=1S/C50H59F3N10O6S/c1-29(31-12-14-32(15-13-31)44-30(2)56-28-70-44)57-47(67)40-23-34(64)26-63(40)48(68)45(49(3,4)5)60-43(65)27-61-18-20-62(21-19-61)33-16-17-38(41(22-33)69-7)59-42-24-39(36(25-55-42)50(51,52)53)58-37-11-9-8-10-35(37)46(66)54-6/h8-17,22,24-25,28-29,34,40,45,64H,18-21,23,26-27H2,1-7H3,(H,54,66)(H,57,67)(H,60,65)(H2,55,58,59)/t29-,34+,40-,45+/m0/s1

SMILES

CC1=C(SC=N1)C2=CC=C(C=C2)C(C)NC(=O)C3CC(CN3C(=O)C(C(C)(C)C)NC(=O)CN4CCN(CC4)C5=CC(=C(C=C5)NC6=NC=C(C(=C6)NC7=CC=CC=C7C(=O)NC)C(F)(F)F)OC)O

Mechanism

Target: GSK215 selectively targets focal adhesion kinase, also known as PTK2 or FAK.

Binding site: Its VS-4718-derived warhead binds the ATP pocket of FAK kinase domain.

Mechanism of action: GSK215 is a VHL-based FAK PROTAC generated by linking the FAK inhibitor VS-4718 to a von Hippel-Lindau E3 ligase ligand. This architecture recruits FAK into a ternary complex with VHL, driving ubiquitination and rapid, sustained proteasomal degradation of the kinase. Because FAK functions as both a catalytic enzyme and adhesion-associated signaling scaffold, GSK215 enables experimental distinction between kinase inhibition and protein depletion. It is useful for investigating focal adhesion signaling, migration-associated pathways, degradation durability, and downstream effects of removing FAK protein from cellular complexes.

Applications

• PROTAC-Mediated Targeted Degradation: GSK215 is utilized for the selective degradation of specific proteins, enabling researchers to study the effects of protein depletion on cellular pathways. This approach provides insights into protein function and aids in identifying potential therapeutic targets by observing phenotypic changes upon protein removal.

• Protein-Protein Interaction Studies: By employing GSK215, scientists can investigate the dynamics of protein-protein interactions through targeted degradation. This method allows for the dissection of complex signaling networks and helps elucidate the role of individual proteins in maintaining cellular homeostasis.

• Mechanistic Pathway Analysis: GSK215 facilitates the exploration of cellular pathways by enabling the degradation of key regulatory proteins. Researchers can use this tool to dissect signaling cascades, identify critical nodes, and understand the mechanistic basis of various biological processes, leading to a deeper comprehension of cellular function.

• Drug Resistance Research: GSK215 is instrumental in studying mechanisms of drug resistance by degrading proteins implicated in resistance pathways. This application helps in identifying vulnerabilities in resistant cancer cells and contributes to the development of strategies to overcome therapeutic resistance.

1. Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode

David N Mallett, James Rowedder, Michael D Goldsmith, Niall A Anderson, Sebastien Campos, Nick Barton, Andrew Sharpe, J Nicole Hamblin, Sorif Uddin, Maire A Convery, Daniel A Thomas, Vipulkumar K Patel, Jana Krause, Douglas W Thomson, Augustin Amour, Edith M Hessel, Christopher D Edwards, Grant A McGonagle, Kenneth Down, Cole Clissold, Srividya Sriskantharajah, Birgit Duempelfeld, Paul Rowland, Edward P Cannons, Kevin Doyle, John J Coward J Med Chem . 2021 Sep 23;64(18):13780-13792. doi: 10.1021/acs.jmedchem.1c01102.

Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound31(GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound31(GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.

2. Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs

John P Evans, Paul Scott-Stevens, John D Harling, Joao Nunes, Markus A Queisser, Antonia J Lewis, Andrew B Benowitz, Chun-Wa Chung, Karol Buda, Peter Stacey, Adam Flinders, Christopher J Tame, Han Dai, Gillian F Watt, Robert P Law, Diana Klimaszewska, Marcus Bantscheff, Marcel Muelbaier, Nico Zinn Angew Chem Int Ed Engl . 2021 Oct 18;60(43):23327-23334. doi: 10.1002/anie.202109237.

Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.

Stock concentration: *

Desired final volume: *

Desired concentration: *

* 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