PF-AKT400 - CAS 1004990-28-6
Catalog number: 1004990-28-6
Category: Inhibitor
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PF-AKT400 is an APT competitor inhibitor of AKR kinase. This compound was first described as compound 42 in J. Med. Chem. 2010, 53, 4615–4622 by a group of Pfizer scientists. The paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development. The compound has no official name, has molecule weight 400.43. We temporally call this compound as PF-AKT400.
PF-AKT400; PFAKT400; Lig1; Lig-1; Lig 1; PF AKT400; AKT-0286; AKT 0286; AKT0286
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1.Binding selectivity studies of PKBα using molecular dynamics simulation and free energy calculations.
Chen SF;Cao Y;Chen JJ;Chen JZ J Mol Model. 2013 Nov;19(11):5097-112. doi: 10.1007/s00894-013-1997-3. Epub 2013 Oct 2.
Designing selective protein kinase B (PKB/Akt) inhibitor is an area of intense research to develop potential anticancer drugs. In the present study, the molecular basis governing PKB-selective inhibition has been investigated using molecular dynamics simulation. The binding free energies calculated by MM/PBSA gave a good correlation with the experimental biological activity and a good explanation of the activity difference of the studied inhibitors. The decomposition of free energies by MM/GBSA indicates that the ethyl group on pyrrolo[2,3-d]pyrimidine ring of inhibitor Lig1 (N-{[(3S)-3-amino-1-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]-methyl}-2,4-difluoro-benzamide) is an important contributor to its PKBα selectivity due to its hydrophobic interaction with the side chain of Thr291 in PKBα. The substituted groups on the pyrrolidine ring of Lig1 also show a strong tendency to mediate protein-ligand interactions through the hydrogen bonds formed between the amino or amide groups of Lig1 and the carboxyl O atoms of Glu234, Glu278, and Asp292 of PKBα. It was reported that there are only three key amino acid differences between PKBα (Thr211, Ala230, Met281) and PKA (Val104, Val123, Leu173) within the clefts of ATP-binding sites.
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CAS 1004990-28-6 PF-AKT400

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