Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors (original) (raw)
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Journal of Biomolecular Structure & Dynamics, 2017
The AKT isoforms are a group of key kinases that play a critical role in tumorigenesis. These enzymes are overexpressed in different types of cancers, such as breast, colon, prostate, ovarian, and lung. Because of its relevance the AKT isoforms are attractive targets for the design of anticancer molecules. However, it has been found that AKT1 and AKT3 isoforms have a main role in tumor progression and metastasis; thus, the identification of AKT isoforms specific inhibitors seems to be a challenge. Previously, we identified an ATP binding pocket pan-AKT inhibitor, this compound is a 2,4,6-trisubstituted pyridine (compound 11), which represents a new interesting scaffold for the developing of AKT inhibitors. Starting from the 2,4,6-trisubstituted pyridine scaffold, and guided by structure-based design technique, 42 new inhibitors were designed and further evaluated in the three AKT isoforms by multiple docking approach and molecular dynamics. Results showed that seven compounds presented binding selectivity for AKT1 and AKT3, better than for AKT2. The binding affinities of these seven compounds on AKT1 and AKT3 isoforms were mainly determined by hydrophobic contributions between the aromatic portion at position 4 of the pyridine ring with residues Phe236/234, Phe237/235, Phe438/435, and Phe442/439 in the ATP binding pocket. Results presented in this work provide an addition knowledge leading to promising selective AKT inhibitors.
In Silico Studies of Indazole Pyridine Analogs as Potent Inhibitors of Akt Protein in Cancer
AKT/Protein kinase B (PKB) signaling cascades are important in both normal cellular physiology and various diseased states, especially its expression is observed as hikes in few cancers. A series of invention of AKT inhibitors lead to the discovery of Indazole pyridine analogues. These analogues are more potent in binding with AKT protein and are ATP competitive. Aim of this study is to identify few indazole pyridine compounds that can effectivelyinhibit AKTprotein activity. Our methods include minimization of analogues with commercial software's like HyperChem 8.0 followed by docking against the target (AKT) using GOLD. From docking analysis, we found that substitutions like Methyl linkage, Thiophene, Thiozole, Imidazole and Amino groups at the third position of indazole pyridine are more efficient in inhibiting the AKT activity. Among all the substituents, Thiophene was found most potent lead and has the highest fitness score of 64.5. Absorption, Distribution, Metabolism, Excr...
Azole-based inhibitors of AKT/PKB for the treatment of cancer
Bioorganic & Medicinal Chemistry Letters, 2010
Through a combination of screening and structure-based rational design, we have discovered a series of N 1 -(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
Synthesis and structure based optimization of novel Akt inhibitors
Bioorganic & Medicinal Chemistry Letters, 2008
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC 50 of 2.4 ± 0.6 nM, Akt cell potency of 50 ± 19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).
Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors
Bioorganic & Medicinal Chemistry, 2006
A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (K i = 0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo.
Journal of Medicinal Chemistry, 2010
Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses. † PDB ID Codes: 2x37 (10-PKB), 2x39 (21-PKB). a Abbreviations: AGC, cAMP-dependent, cGMP-dependent and protein kinase C; ELISA, enzyme-linked immunosorbent assay; mTOR, mammalian target of rapamycin; PH, pleckstrin homology; PKA, protein kinase A; PKB, protein kinase B; PI3K, phosphatidylinositol-3 kinase; PI(3,4,5)P 3 , phosphatidylinositol-3,4,5 triphosphate; PTEN, phosphatase and tensin homologue.
Pharmaceutics
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is globally poor. In more than 60% of AML patients, the PI3K/AKTs/mTOR signaling pathway is aberrantly activated because of oncogenic driver alterations and further enhanced by chemotherapy as a mechanism of drug resistance. Against this backdrop, very recently we have started a multidisciplinary research project focused on AKT1 as a pharmacological target to identify novel anti-AML agents. Indeed, the serendipitous finding of the in-house compound T187 as an AKT1 inhibitor has paved the way to the rational identification of new active small molecules, among which T126 has emerged as the most interesting compound with IC50 = 1.99 ± 0.11 μM, ligand efficiency of 0.35, and a clear effect at low micromolar concentrations on growth inhibition and induction of apoptosis in AML cells. The collected results together with preliminary SAR data strongly indicate that the 5,6,7,8-tetrahydrobenzo[4,5]thieno...
Journal of Medicinal Chemistry, 2012
This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.