"目录号: HY-13917
Protein Tyrosine Kinase/RTK-
PND-1186 可逆地抑制FAK活性，IC50为 1.5 nM。
FAK
相关产品
Defactinib-GSK2256098-NVP-TAE 226-PF-573228-PF-562271-CEP-37440-Y15-PF-431396-NAMI-A-
生物活性
Description
PND-1186 is a substituted pyridine reversible inhibitor ofFAKactivity withIC50of 1.5 nM in vitro.
IC50& Target
IC50: 1.5 nM (FAK)[1]
In Vitro
Using the recombinant FAK kinase domain as a glutathione-S-transferase (GST) fusion protein in an in vitro kinase assay, PND-1186 inhibits FAK activity with IC50of 1.5 nM. PND-1186 has an IC50of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. Whereas 1.0 μM PND-1186 (>5-fold above IC50) has limited effects on cell proliferation, under non-adherent conditions or when grown as spheroids or colonies in soft agar, 0.1 μM PND-1186 blocks FAK and p130Cas tyrosine phosphorylation, promotes caspase-3 activation, and triggers cell apoptosis. PND-1186 inhibits 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activation[1].
In Vivo
100 mg/kg PND-1186 treatment significantly reduces final 4T1 tumor weight 2-fold (n=8, p<0.05) whereas 30 mg/kg PND-1186 slightly reduces final tumor weight but is not significantly different compare to control (n=8, p>0.05). Both 30 and 100 mg/kg administration of PND-1186 significantly increases tumor TUNEL staining compare to vehicle-treated controls. As elevated cleaved caspase-3 staining is also found in the tumors of PND-1186-treated mice[1]. PND-1186 displays a multi-exponential decay with a terminal half life (t1/2) of 1.72 hours after i.v. injection. Following i.p. and p.o. dosing, PND-1186 is rapidly absorbed with terminal half lives (t1/2) of 2.15 to 2.65 h, and bioavailability (%F) from 14.8 to 42.2%. PND-1186 bioavailability is greater upon intraperitoneal versus oral dosing[2].
Clinical Trial
NCT01849744
Verastem, Inc.
Non Hematologic Cancers-Metastatic Cancer
June 2013
Phase 1
NCT02215629
Verastem, Inc.
Relapsed or Refractory Acute Myeloid Leukemia-Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia
Phase 1
NCT02651727
Verastem, Inc.
Pancreatic Cancer
September 2015
Phase 1
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References
[1].Tanjoni I, et al. PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer Biol Ther. 2010 May 15;9(10):764-77.
[2].Walsh C, et al. Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer Biol Ther. 2010 May 15;9(10):778-90.