1221186-53-3 Usage
Description
Pyruvate kinase catalyzes the final step in glycolysis, the formation of pyruvate and ATP from phosphoenolpyruvate and ADP. The expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in the metabolic reprogramming of tumor cells, which require high amounts of glucose for proliferation. PKM2 is allosterically regulated by the upstream glycolytic intermediate, fructose-1,6-bisphosphate (FBP), which controls glycolysis in a feed forward mechanism. Whereas cancer cells exist in highly phosphorylated states, the binding of certain peptide motifs with phosphorylated tyrosines can inhibit PKM2 activity by causing the release of FBP from the allosteric site. ML-265 activates tumor-specific PKM2 (EC50 = 92 nM) by binding to the dimer-dimer interface between two subunits of PKM2 and inducing tetramerization, which is the most active form of the enzyme. It demonstrates >100-fold selectivity for PKM2 over the related PKM1, PKR, and PKL isoforms. At 50 mg/kg, ML-265 has been shown to reduce tumor size, weight, and occurrence in mice bearing H1299 cell xenografts in a model of human non-small cell lung carcinoma.
references
[1]. anastasiou d, yu y, israelsen wj, et al. pyruvate kinase m2 activators promote tetramer formation and suppress tumorigenesis. nat chem biol. 2012 oct;8(10):839-47.[2]. walsh mj, brimacombe kr, anastasiou d, et al. ml265: a potent pkm2 activator induces tetramerization and reduces tumor formation and size in a mouse xenograft model. probe reports from the nih molecular libraries program [internet].
Check Digit Verification of cas no
The CAS Registry Mumber 1221186-53-3 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,2,1,1,8 and 6 respectively; the second part has 2 digits, 5 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 1221186-53:
(9*1)+(8*2)+(7*2)+(6*1)+(5*1)+(4*8)+(3*6)+(2*5)+(1*3)=113
113 % 10 = 3
So 1221186-53-3 is a valid CAS Registry Number.
1221186-53-3Relevant articles and documents
Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase
Jiang, Jian-kang,Boxer, Matthew B.,Vander Heiden, Matthew G.,Shen, Min,Skoumbourdis, Amanda P.,Southall, Noel,Veith, Henrike,Leister, William,Austin, Christopher P.,Park, Hee Won,Inglese, James,Cantley, Lewis C.,Auld, Douglas S.,Thomas, Craig J.
supporting information; experimental part, p. 3387 - 3393 (2010/08/20)
Cancer cells have distinct metabolic needs that are different from normal cells and can be exploited for development of anti-cancer therapeutics. Activation of the tumor specific M2 form of pyruvate kinase (PKM2) is a potential strategy for returning cancer cells to a metabolic state characteristic of normal cells. Here, we describe activators of PKM2 based upon a substituted thieno[3,2-b]pyrrole[3,2-d]pyridazinone scaffold. The synthesis of these agents, structure-activity relationships, analysis of activity at related targets (PKM1, PKR and PKL) and examination of aqueous solubility are investigated. These agents represent the second reported chemotype for activation of PKM2.