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

IUPACName

N-(2-hydroxyethyl)-3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzamide

Synonyms

GNF-5; GNF 5; GNF5.

InChI Key

IIQUYGWWHIHOCF-UHFFFAOYSA-N

InChI

InChI=1S/C20H17F3N4O3/c21-20(22,23)30-16-6-4-15(5-7-16)27-18-11-17(25-12-26-18)13-2-1-3-14(10-13)19(29)24-8-9-28/h1-7,10-12,28H,8-9H2,(H,24,29)(H,25,26,27)

SMILES

C1=CC(=CC(=C1)C(=O)NCCO)C2=CC(=NC=N2)NC3=CC=C(C=C3)OC(F)(F)F

Mechanism

Target: This ligand targets ABL1 myristoyl allosteric pocket in biochemical or cellular target-engagement studies.

Mechanism of Action: Used as the target-protein recognition element, this ligand provides the binding interface for ABL1 myristoyl allosteric pocket. In PROTAC design, a derivatizable position on the ligand can be connected through an optimized linker to an E3 ligase ligand, such as a CRBN, VHL, or IAP recruiter, while preserving productive target engagement. The resulting bifunctional molecule brings ABL1 myristoyl allosteric pocket into proximity with the recruited E3 ligase, enabling ternary-complex formation. If the complex has favorable geometry and residence time, target lysine ubiquitination is promoted, leading to proteasome-dependent degradation in experimental systems.

Applications

• PROTAC Ligand for Degradation: GNF-5 can be used as a recruiting or binding ligand within PROTAC constructs to engage a chosen E3 ligase and promote ubiquitination of the target protein. This enables systematic evaluation of how ligand affinity, linker length, and ternary complex formation influence targeted protein degradation efficiency and kinetics in cellular assays.

• Ternary Complex Optimization: In PROTAC development, GNF-5–based chimeras can be leveraged to probe ternary complex stability between the target protein, the E3 ligase, and the PROTAC. By varying conjugation sites and linker geometry, researchers can quantify changes in binding cooperativity that correlate with degradation potency and selectivity.

• Pathway Mechanism Studies: GNF-5–derived PROTACs are suitable tools for dissecting degradation-driven pathway remodeling. Researchers can apply these constructs to determine whether loss of the target protein alters downstream signaling, transcriptional programs, or phenotypic outputs, distinguishing degradation effects from transient inhibition using time-course and washout experiments.

• Target Selectivity Profiling: Incorporating GNF-5 into PROTACs supports comparative studies across related targets and isoforms to map degradation selectivity. Systematic panel testing combined with proteomics can reveal off-target degradation events, helping refine ligand choice and PROTAC architecture to maximize on-target degradation while minimizing unintended protein loss.

1.NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors.

Skora L;Mestan J;Fabbro D;Jahnke W;Grzesiek S Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4437-45. doi: 10.1073/pnas.1314712110. Epub 2013 Nov 4.

Successful treatment of chronic myelogenous leukemia is based on inhibitors binding to the ATP site of the deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl) fusion protein. Recently, a new type of allosteric inhibitors targeting the Abl myristoyl pocket was shown in preclinical studies to overcome ATP-site inhibitor resistance arising in some patients. Using NMR and small-angle X-ray scattering, we have analyzed the solution conformations of apo Abelson tyrosine kinase (c-Abl) and c-Abl complexes with ATP-site and allosteric inhibitors. Binding of the ATP-site inhibitor imatinib leads to an unexpected open conformation of the multidomain SH3-SH2-kinase c-Abl core, whose relevance is confirmed by cellular assays on Bcr-Abl. The combination of imatinib with the allosteric inhibitor GNF-5 restores the closed, inactivated state. Our data provide detailed insights on the poorly understood combined effect of the two inhibitor types, which is able to overcome drug resistance.

2.Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors.

Meirson T;Genna A;Lukic N;Makhnii T;Alter J;Sharma VP;Wang Y;Samson AO;Condeelis JS;Gil-Henn H Oncotarget. 2018 Apr 24;9(31):22158-22183. doi: 10.18632/oncotarget.25243. eCollection 2018 Apr 24.

Metastatic dissemination of cancer cells from the primary tumor and their spread to distant sites in the body is the leading cause of mortality in breast cancer patients. While researchers have identified treatments that shrink or slow metastatic tumors, no treatment that permanently eradicates metastasis exists at present. Here, we show that the ABL kinase inhibitors imatinib, nilotinib, and GNF-5 impede invadopodium precursor formation and cortactin-phosphorylation dependent invadopodium maturation, leading to decreased actin polymerization in invadopodia, reduced extracellular matrix degradation, and impaired matrix proteolysis-dependent invasion. Using a mouse xenograft model we demonstrate that, while primary tumor size is not affected by ABL kinase inhibitors, the ;in vivo; matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs are significantly impaired in inhibitor-treated mice. Further proteogenomic analysis of breast cancer patient databases revealed co-expression of the Abl-related gene (Arg) and cortactin across all hormone- and human epidermal growth factor receptor 2 (HER2)-receptor status tumors, which correlates synergistically with distant metastasis and poor patient prognosis.

3.Role of Abl in airway hyperresponsiveness and airway remodeling.

Cleary RA;Wang R;Wang T;Tang DD Respir Res. 2013 Oct 11;14:105. doi: 10.1186/1465-9921-14-105.

BACKGROUND: ;Asthma is a chronic disease that is characterized by airway hyperresponsiveness and airway remodeling. The underlying mechanisms that mediate the pathological processes are not fully understood. Abl is a non-receptor protein tyrosine kinase that has a role in the regulation of smooth muscle contraction and smooth muscle cell proliferation in vitro. The role of Abl in airway hyperresponsiveness and airway remodeling in vivo is largely unknown.;METHODS: ;To evaluate the role of Abl in asthma pathology, we assessed the expression of Abl in airway tissues from the ovalbumin sensitized and challenged mouse model, and human asthmatic airway smooth muscle cells. In addition, we generated conditional knockout mice in which Abl expression in smooth muscle was disrupted, and then evaluated the effects of Abl conditional knockout on airway resistance, smooth muscle mass, cell proliferation, IL-13 and CCL2 in the mouse model of asthma. Furthermore, we determined the effects of the Abl pharmacological inhibitors imatinib and GNF-5 on these processes in the animal model of asthma.;RESULTS: ;The expression of Abl was upregulated in airway tissues of the animal model of asthma and in airway smooth muscle cells of patients with severe asthma.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
1 mM	2.3902 mL	11.9511 mL	23.9023 mL
5 mM	0.4780 mL	2.3902 mL	4.7805 mL
10 mM	0.2390 mL	1.1951 mL	2.3902 mL
50 mM	0.0478 mL	0.2390 mL	0.4780 mL

GNF-5 is a ABL/Src-family kinase target ligand intended for use as the target-engaging component or reference ligand in PROTAC discovery workflows. Its known small-molecule recognition profile enables rational linker-vector evaluation and comparative degrader design. This molecule is described in detail below.

Structure: The structure of GNF-5 is characterized by amide/urea/sulfonamide hydrogen-bonding motifs; phenol or alcohol functionality; halogenated aryl/heteroaryl ring system; heteroaromatic protein-recognition scaffold. These features provide defined hydrogen-bonding, hydrophobic, and steric elements that can support affinity retention while enabling analogue-based linker-vector selection.

Reactivity: The hydroxy or phenolic motif can be considered for ether, carbonate, carbamate, or ester linker attachment after SAR verification. For PROTAC construction, the POI ligand can be paired with CRBN ligands such as thalidomide, pomalidomide, or lenalidomide analogues, VHL ligands such as VH032 derivatives, or less common IAP/MDM2/cIAP-recruiting ligands, with alkyl, PEG, piperazine, triazole, or amide linkers screened for ternary-complex formation. In practice, incorporation into PROTACs should begin from derivatives that preserve the reported binding pharmacophore, followed by systematic variation of linker length, polarity, rigidity, and exit-vector geometry to optimize target engagement, E3 recruitment, and cellular degradation readouts.

What is the solubility of GNF-5? can you give me an introduction? thanks.

DMSO : 83 mg/mL Ethanol : 20 mg/mL Water : Insoluble

10/6/2020

Good evening, what is the bioactivity of GNF-5? thank you.

Here's a breakdown of its known activities: 1. Selective Allosteric Bcr-Abl Inhibition: GNF-5 acts as a selective allosteric inhibitor of Bcr-Abl, meaning it binds to a site distinct from the ATP-binding pocket used by conventional Bcr-Abl inhibitors. This leads to a different mode of inhibition, potentially offering advantages like: Overcoming resistance: GNF-5 may be effective against Bcr-Abl mutations resistant to traditional inhibitors. Reduced side effects: By targeting a different site, GNF-5 might exhibit a different side effect profile compared to conventional inhibitors. 2. Additional Activities: GNF-5's bioactivity extends beyond Bcr-Abl inhibition, showcasing potential for broader therapeutic applications: Inhibits viral fusion: Studies suggest GNF-5 can block the fusion of certain viruses, like the infectious bronchitis virus, into host cells, potentially offering antiviral properties. Improves survival in Bcr-Abl-driven cancers: In combination with other Bcr-Abl inhibitors, GNF-5 has shown promise in enhancing survival in mouse models of Bcr-Abl-driven cancers. Anti-inflammatory effects: GNF-5 might possess anti-inflammatory properties through its interaction with other cellular signaling pathways. 3. Current Stage of Development: GNF-5 is still under investigation, with preclinical and early clinical studies ongoing. While it shows promising potential, further research is needed to fully understand its safety, efficacy, and long-term benefits in various clinical settings.

3/9/2021

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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