212631-67-9 Usage
Description
PD 184161 is a cell-permeable, blood-brain barrier permeant, and orally active hydroxamate compound. It is a novel mitogen-activated protein kinase kinase (MEK) inhibitor that has been shown to exhibit antitumor effects and suppress MEK-extracellular signal-related kinase signaling activity and cell proliferation in human hepatocellular carcinoma cells and in human hepatocellular carcinoma xenografts. PD 184161 is also known for its excellent selectivity over 27 other cellular kinases and its ability to induce necrosis in several types of glucose-deprived cells via an indirect action on the F0 component of the mitochondrial F1F0-ATPase/synthase. It is an off-white solid.
Uses
Used in Pharmaceutical Industry:
PD 184161 is used as an MEK inhibitor for its antitumor effects and suppression of MEK-extracellular signal-related kinase signaling activity and cell proliferation in human hepatocellular carcinoma cells and xenografts.
Used in Cancer Research:
PD 184161 is used as a research tool to study the role of MEK in cancer cell proliferation and signaling pathways, as well as to test its potential synergistic effects with other chemotherapeutic drugs.
Used in Drug Development:
PD 184161 is used in the development of novel drug delivery systems to enhance its applications and efficacy against cancer cells, employing various organic and metallic nanoparticles as carriers for improved delivery, bioavailability, and therapeutic outcomes.
Biological Activity
pd 184161 is a mek1/2 inhibitor.the intracellular signaling pathway of mitogen-activated protein kinases is involved in the regulation of various cellular functions. one of these pathways, named raf/mek/erk pathway, plays a key role in the regulation of cellular differentiation, growth, and proliferation. the modulation of this raf/mek/erk pathway has been reported as a useful approach to treate proliferative disorders such as cancer.
Biochem/physiol Actions
PD-184161 is a MEK inhibitor.
in vitro
previous study found that pd184161 could inhibit mek activity in a time- and concentration-dependent manner, which was more effectively than pd098059 or u0126. moreover, pd184161 could inhibit cell proliferation and induce apoptosis at concentrations of > or = 1.0 μm time- and concentration-dependently [1].
in vivo
animal study showd that tumor xenograft p-erk levels were significantly reduced 3 to 12 hours after an oral dose of pd184161. contrarily, tumor xenograft p-erk levels following long-term treatment of pd184161 were refractory to this signaling effect. pd184161 also significantly suppressed tumor engraftment and initial growth, however, established tumors were not significantly affected. in summary, pd184161 has antitumor effects in hcc in vivo that appear to correlate with suppression of mek activity [1].
IC 50
10-100 nm
references
[1] klein, p. j.,schmidt, c.m.,wiesenauer, c.a., et al. the effects of a novel mek inhibitor pd184161 on mek-erk signaling and growth in human liver cancer. neoplasia 8(1), 1-8 (2006).
Check Digit Verification of cas no
The CAS Registry Mumber 212631-67-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,1,2,6,3 and 1 respectively; the second part has 2 digits, 6 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 212631-67:
(8*2)+(7*1)+(6*2)+(5*6)+(4*3)+(3*1)+(2*6)+(1*7)=99
99 % 10 = 9
So 212631-67-9 is a valid CAS Registry Number.
212631-67-9Relevant articles and documents
The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901
Barrett, Stephen D.,Bridges, Alexander J.,Dudley, David T.,Saltiel, Alan R.,Fergus, James H.,Flamme, Cathlin M.,Delaney, Amy M.,Kaufman, Michael,LePage, Sophie,Leopold, Wilbur R.,Przybranowski, Sally A.,Sebolt-Leopold, Judith,Van Becelaere, Keri,Doherty, Annette M.,Kennedy, Robert M.,Marston, Dan,Howard Jr., W. Allen,Smith, Yvonne,Warmus, Joseph S.,Tecle, Haile
supporting information; experimental part, p. 6501 - 6504 (2009/10/01)
A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzam ide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-b enzamide PD 0325901.
