1429881-91-3 Usage
Description
UNC2025 is a potent, orally bioavailable inhibitor of the tyrosine kinases Mer and Flt3, with IC50s of 0.74 and 0.80 nM, respectively. It also less potently inhibits Axl and Tyro3 with IC50s of 14 and 17 nM, respectively. UNC2025 is effective in blocking colony formation of Merand Flt3-dependent tumor cell lines and inhibits Mer phosphorylation in bone marrow leukemia cells in vivo. Pharmacokinetic studies indicate that orally administered UNC2025 at 3 mg/kg can provide 90% inhibition of Mer and Flt3 at 30 minutes.
Uses
Used in Biological Studies:
UNC2025 is used as a Mer/FLT3 dual inhibitor for biological research, particularly in the study of tyrosine kinases and their role in tumor cell lines and bone marrow leukemia cells.
Used in Oncology:
In the field of oncology, UNC2025 is used as a novel MERTK inhibitor to induce polyploidy and promote death and senescence in human glioblastoma multiforme cells. High levels of GAS6 MERTK ligand expression in these cells have been correlated with decreased overall survival in patients, making UNC2025 a potential therapeutic agent for glioblastoma treatment.
in vitro
in duplicate versus 305 kinases at carna biosciences using a microcapillary electrophoresis assay, unc2025 inhibited mer and flt3 with the greatest potency. in b-all 697 cell lysates using the atp activx probe assay, unc2025 inhhibited the activity of mer with an ic50 of 0.05 nm. in 697 b-all cells, unc2025 potently inhibited mer phosphorylation with an ic50 of 2.7 nm. similarly, in flt3-itd positive molm-14 acute myeloid leukemia cells, treatment with unc2025 decreased phosphorylation of flt3 with an ic50 of 14 nm. in soft agar cultures of the a549 nsclc and molm-14 aml cell lines, incubation withunc2025 significantly inhibited colony formation, which was known to depend on merand flt3,respectively, for optimal expression of oncogenic phenotypes. much higher concentrations of unc2025 were required to effectively inhibit phosphorylation of axl (ic50 = 122 nm) and tyro3 (ic50 = 301 nm)[1].
in vivo
in mice with human leukemia xenografts, a single dose of unc2025 (3 mg/kg) administered orally was sufficient to decrease merphospho-protein levels in bone marrow leukemia cells by greater than 90% [1].
references
[1]. zhang w1,deryckere d,hunter d,liu j,stashko ma,minson ka, et,al. unc2025, a potent and orally bioavailablemer/flt3dual inhibitor.j med chem.2014 aug 28;57(16):7031-41. doi: 10.1021/jm500749d. epub 2014 aug 6.
Check Digit Verification of cas no
The CAS Registry Mumber 1429881-91-3 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,4,2,9,8,8 and 1 respectively; the second part has 2 digits, 9 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 1429881-91:
(9*1)+(8*4)+(7*2)+(6*9)+(5*8)+(4*8)+(3*1)+(2*9)+(1*1)=203
203 % 10 = 3
So 1429881-91-3 is a valid CAS Registry Number.
1429881-91-3Relevant articles and documents
UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor
Zhang, Weihe,Deryckere, Deborah,Hunter, Debra,Liu, Jing,Stashko, Michael A.,Minson, Katherine A.,Cummings, Christopher T.,Lee, Minjung,Glaros, Trevor G.,Newton, Dianne L.,Sather, Susan,Zhang, Dehui,Kireev, Dmitri,Janzen, William P.,Earp, H. Shelton,Graham, Douglas K.,Frye, Stephen V.,Wang, Xiaodong
, p. 7031 - 7041 (2014)
We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.