A Structural Comparison of Inhibitor Binding to PKB, PKA and PKA-PKB Chimera

Davies, Thomas G.; Verdonk, Marcel L.; Graham, Brent; Saalau-Bethell, S.; Hamlett, C.C.F.; McHardy, T.; Collins, Ian; Garrett, Michelle D.; Workman, Paul; Woodhead, Steven J.; Jhoti, Harren; Barford, David

doi:10.1016/j.jmb.2007.01.004

Cited by 82 publications

(68 citation statements)

References 53 publications

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“…Recently, the PI3K/AKT signal transduction pathway has become the focus of intense interest as a critical regulator of tumor cell survival, and a number of AKT pathway inhibitors have been disclosed with a wide variety of potencies and specificities (2,44,45). In this report, we describe the in vitro and in vivo effects of AT7867, a recently developed inhibitor of AKT and p70S6K, which has been identified using fragment-based lead discovery and structure-based design technologies (29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

“…These fragments were validated by structural studies and rapidly transformed into potent lead compounds using structure-based design to increase the efficiency of the medicinal chemistry. This research was recently described in detail and has identified potent, low molecular weight inhibitors of AKT that exhibit drug-like properties (29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

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AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth

Grimshaw

Hunter

Yap

et al. 2010

Molecular Cancer Therapeutics

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The serine/threonine kinase AKT plays a pivotal role in signal transduction events involved in malignant transformation and chemoresistance and is an attractive target for the development of cancer therapeutics. Fragment-based lead discovery, combined with structure-based drug design, has recently identified AT7867 as a novel and potent inhibitor of both AKT and the downstream kinase p70 S6 kinase (p70S6K) and also of protein kinase A. This ATP-competitive small molecule potently inhibits both AKT and p70S6K activity at the cellular level, as measured by inhibition of GSK3β and S6 ribosomal protein phosphorylation, and also causes growth inhibition in a range of human cancer cell lines as a single agent. Induction of apoptosis was detected by multiple methods in tumor cells following AT7867 treatment. Administration of AT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) to athymic mice implanted with the PTEN-deficient U87MG human glioblastoma xenograft model caused inhibition of phosphorylation of downstream substrates of both AKT and p70S6K and induction of apoptosis, confirming the observations made in vitro. These doses of AT7867 also resulted in inhibition of human tumor growth in PTEN-deficient xenograft models. These data suggest that the novel strategy of AKT and p70S6K blockade may have therapeutic value and supports further evaluation of AT7867 as a singleagent anticancer strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth

Grimshaw

Hunter

Yap

et al. 2010

Molecular Cancer Therapeutics

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“…A-443654 shows some level of selectivity against other members of the AGC family: PKA, 40-fold; PKCg, 150-fold; PKCd, 200 and PDK1, >120 000-fold (Luo et al, 2005). A structural comparison of A-443654 bound to Akt and PKA demonstrated that the compound adopts a binding conformation in Akt that differs from that with PKA (Davies et al, 2007). In particular, the reported differences in potency of A-443654 for Akt compared with PKA seem to arise as a result of one of the three key residue differences between the ATPbinding clefts: namely the presence of methione-282 in place of leucine at the base of the Akt cleft.…”

Section: Inhibitors Of the Ser/thr Kinase Activity Of Aktmentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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“…There is clearly no density for the phosphate group at Ser-181 and residue Ser-177 is completely disordered. When compared with those in the pep- tide-bound active kinase structures (31,32), the unphosphorylated activation loop is clearly in the "off" conformation as it sterically occludes substrate access to the catalytic site. Besides these differences, the rest of the unphosphorylated KD in hIKK␤ shows features of an active kinase.…”

Section: Analysis Of Protein Constructs and Crystallization-twomentioning

confidence: 99%

Crystal Structure of a Human IκB Kinase β Asymmetric Dimer

Liu

Misquitta

Olland

et al. 2013

Journal of Biological Chemistry

125

141

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Background: IB kinase ␤ is a key regulator in the NB signaling pathway. Results: Crystal structure of a human IKK␤ asymmetric dimer shows one kinase active site phosphorylated and in the active conformation and the other unphosphorylated and inactive. Conclusion: Depending on the phosphorylation state, IKK␤ can adopt distinct dimeric geometry. Significance: High resolution structure of hIKK␤ provides structural basis for its activation and potential use of inhibitor design.

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A Structural Comparison of Inhibitor Binding to PKB, PKA and PKA-PKB Chimera

Cited by 82 publications

References 53 publications

AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth

AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Crystal Structure of a Human IκB Kinase β Asymmetric Dimer

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