GNF-2

Names

[ Name ]:
GNF-2

[Synonym ]:
Benzamide, 3-[6-[[4-(trifluoromethoxy)phenyl]amino]-4-pyrimidinyl]-
3k5v
3-(6-{[4-(Trifluoromethoxy)phenyl]amino}-4-pyrimidinyl)benzamide
GNF-2
Bcr-abl Inhibitor

Biological Activity

[Description]:

GNF-2 is a highly selective non-ATP competitive inhibitor of oncogenic Bcr-Abl activity (IC50 = 0.14 μM).IC50 value: 0.14 uM [1]Target: Bcr-Ablin vitro: Ba/F3 cells harboring native or T315I mutated Bcr-Abl constructs were treated with GNF-2 and AKIs. We monitored the effect of GNF-2 with AKIs on the proliferation and clonigenicity of the different Ba/F3 cells. In addition, we monitored the auto-phosphorylation activity of Bcr-Abl and JAK2 in cells treated with GNF-2 and AKIs [2]. GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner [3].GNF-2 dose-dependently inhibited the proliferation of osteoclast precursors through the suppression of the M-CSFR c-Fms. In addition, GNF-2 accelerated osteoclast apoptosis by inducing caspase-3 and Bim expression. Furthermore, GNF-2 interfered with actin cytoskeletal organization and subsequently blocked the bone-resorbing activity of mature osteoclasts [4].in vivo: Combining PDMP and GNF-2 eliminated transplanted-CML-T315I-mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis[5].

[Related Catalog]:

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> Bcr-Abl

Research Areas >> Cancer

[References]

[1]. Adrián FJ, et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol. 2006 Feb;2(2):95-102.

[2]. Khateb M, et al. Overcoming Bcr-Abl T315I mutation by combination of GNF-2 and ATP competitors in an Abl-independent mechanism. BMC Cancer. 2012 Nov 27;12:563.

[3]. Mian AA, et al. Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I.BMC Cancer. 2012 Sep 17;12:411.

[4]. Kim HJ, et al. The tyrosine kinase inhibitor GNF-2 suppresses osteoclast formation and activity. J Leukoc Biol. 2013 Oct 15.

[5]. Huang WC, et al. Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. FASEB J. 2011 Oct;25(10):3661-73.

[Related Small Molecules]

Nocodazole | Asciminib | Degrasyn(WP1130) | Bafetinib (INNO-406) | DCC-2036 (Rebastinib) | KW-2449 | AST 487 | PD173955 | XL228 | DPH | GNF-7 | GZD824 | Flumatinib | GNF-5 | Radotinib

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
536.4±50.0 °C at 760 mmHg

[ Molecular Formula ]:
C₁₈H₁₃F₃N₄O₂

[ Molecular Weight ]:
374.317

[ Flash Point ]:
278.2±30.1 °C

[ Exact Mass ]:
374.099060

[ PSA ]:
90.13000

[ LogP ]:
3.68

[ Appearance of Characters ]:
off-white

[ Vapour Pressure ]:
0.0±1.4 mmHg at 25°C

[ Index of Refraction ]:
1.611

[ Storage condition ]:
2-8°C

[ Water Solubility ]:
H2O: <2mg/mL

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS07

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H315-H319-H335

[ Precautionary Statements ]:
P261-P305 + P351 + P338

[ Personal Protective Equipment ]:
dust mask type N95 (US);Eyeshields;Gloves

[ Hazard Codes ]:
Xi

[ Risk Phrases ]:
36/37/38

[ Safety Phrases ]:
26

[ RIDADR ]:
NONH for all modes of transport

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Articles

Allosteric inhibitors of Bcr-abl-dependent cell proliferation.

Nat. Chem. Biol. 2 , 95-102, (2006)

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activit...

Inhibitors of Bcr-abl... breaking new ground again.

Nat. Chem. Biol. 2nd ed.,, 63-64, (2006)

Related Compounds

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