AKT crystal structure and AKT-specific inhibitors

Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Oncogene (Impact Factor: 8.46). 12/2005; 24(50):7493-501. DOI: 10.1038/sj.onc.1209087
Source: PubMed


AKT kinases are attractive targets for small molecule drug discovery because of their key role in tumor cell survival/proliferation and their overexpression/activation in many human cancers. This review summarizes studies that support the rationale for targeting AKT kinases in new drug discovery efforts. Structural features of AKT kinase in its inactive and active states, as determined by crystal structure analysis, are described. Recent efforts in the development and biological evaluation of small molecule inhibitors of AKT, and the challenges remaining are summarized. Inhibitors targeting the ATP binding site, PH domain and protein substrate binding site, as well as isoform selective allosteric inhibitors are reviewed. Structure-based design using PKA mutants as surrogates and computer modeling in the discovery of selective inhibitors is discussed. The issues and challenges facing the development of different classes of inhibitors as therapeutics are also discussed.

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    • "However, targeting the catalytic domain of these enzymes to develop inhibitor remained quite challenging. For example, several potent inhibitors of AKT1 enzyme turn out to be relatively toxic, presumably due to the inhibition of other ser/threonine kinases [20] [43]. On the other hand, small molecules such as DPIEL and perifosine developed for the inhibition of PIP/PH-domain interaction are comparatively nontoxic and offer a better therapeutic strategy than inhibitors for ATP-site [21] [41]. "
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    ABSTRACT: Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is an important regulator of several cellular processes and a precursor for other second messengers which are involved in cell signaling pathways. Signaling proteins preferably interact with PI(4,5)P2 through its pleckstrin homology (PH) domain. Efforts are underway to design small molecule-based antagonist, which can specifically inhibit the PI(4,5)P2/PH-domain interaction to establish an alternate strategy for the development of drug(s) for phosphoinositide signaling pathways.
    05/2015; 2. DOI:10.1016/j.bbrep.2015.05.007
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    • "Akt/PKB kinases are attractive targets for drug discovery due to their key role in tumor cell survival or proliferation and to their overexpression or activation in many cancers. Small molecule inhibitors targeting the Akt signaling pathway are very promising therapeutics against cancer (Kumar and Madison, 2005; Pal et al., 2010). In this study, we have tested a new panel of commercial inhibitors for various PKs and we analyzed their effects on pairing and egg production by schistosomes as well as their toxicity towards schistosomula larvae of S. mansoni. "
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    ABSTRACT: Protein kinases (PKs) are one of the largest protein families in most eukaryotic organisms. These enzymes are involved in the control of cell proliferation, differentiation and metabolism and a large number of the anticancer drugs currently used are directed against PKs. The structure and function of PKs are well conserved throughout evolution. In schistosome parasites, PKs were shown to be involved in essential functions at every stage of the parasite life cycle, making these enzymes promising anti-parasite drug targets. In this study, we tested a panel of commercial inhibitors for various PKs and analyzed their effects on pairing and egg production by schistosomes as well as their toxicity towards schistosomula larvae. Results obtained confirmed the deleterious effect of PK targeting on Schistosoma mansoni physiology and the important function of different tyrosine and serine/threonine kinases in the biology and reproduction of this parasite. They also indicated for the first time that the Protein kinase B (also called Akt) which is a major downstream target of many receptor tyrosine kinases and a central player at the crossroads of signal transduction pathways activated in response to growth factors and insulin, can constitute a novel target for anti-schistosome chemotherapy. Structural and functional studies have shown that SmAkt is a conserved kinase and that its activity can be inhibited by commercially available Akt inhibitors. In treated adult worms, Akt/PKB kinase pathway inhibitors induced profound alterations in pairing and egg laying and they also greatly affected the viability of schistosomula larvae.
    International Journal for Parasitology: Drugs and Drug Resistance 10/2014; 4(3). DOI:10.1016/j.ijpddr.2014.09.004 · 3.29 Impact Factor
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    • "Aberrant Akt signaling was found in several human diseases, ranging from cancer to metabolic dysfunction and mental diseases [5]. To date, three mammalian isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ), have been identified; all three share a high degree of sequence and structural similarities [6]. These Akt isoforms show differences in tissue-specific expression patterns and play distinct physiological roles with some overlapping functions [5], [7], [8]. "
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    ABSTRACT: Akt1 is well known for its role in regulating cell proliferation, differentiation, and apoptosis and is implicated in tumors and several neurological disorders. However, the role of Akt1 in neural development has not been well defined. We have isolated zebrafish akt1 and shown that this gene is primarily transcribed in the developing nervous system, and its spatiotemporal expression pattern suggests a role in neural differentiation. Injection of akt1 morpholinos resulted in loss of neuronal precursors with a concomitant increase in post-mitotic neurons, indicating that knockdown of Akt1 is sufficient to cause premature differentiation of neurons. A similar phenotype was observed in embryos deficient for Notch signaling. Both the ligand (deltaA) and the downstream target of Notch (her8a) were downregulated in akt1 morphants, indicating that Akt1 is required for Delta-Notch signaling. Furthermore, akt1 expression was downregulated in Delta-Notch signaling-deficient embryos and could be induced by constitutive activation of Notch signaling. In addition, knockdown of Akt1 was able to nullify the inhibition of neuronal differentiation caused by constitutive activation of Notch signaling. Taken together, these results provide in vivo evidence that Akt1 interacts with Notch signaling reciprocally and provide an explanation of why Akt1 is essential for the inhibition of neuronal differentiation.
    PLoS ONE 01/2013; 8(1):e54262. DOI:10.1371/journal.pone.0054262 · 3.23 Impact Factor
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