akt-i-1-2-compound and Neoplasms

ATPases Associated with Diverse Cellular Activity (AAA ATPase) are essential enzymes found in all organisms. They are involved in various processes such as DNA replication, protein degradation, membrane fusion, microtubule serving, peroxisome biogenesis, signal transduction, and the regulation of gene expression. Due to the importance of AAA ATPases, several researchers identified and developed small-molecule inhibitors against these enzymes. We discuss six AAA ATPases that are potential drug targets and have well-developed inhibitors. We compare available structures that suggest significant differences of the ATP binding pockets among the AAA ATPases with or without ligand. The distances from ADP to the His20 in the His-Ser-His motif and the Arg finger (Arg353 or Arg378) in both RUVBL1/2 complex structures bound with or without ADP have significant differences, suggesting dramatically different interactions of the binding site with ADP. Taken together, the inhibitors of six well-studied AAA ATPases and their structural information suggest further development of specific AAA ATPase inhibitors due to difference in their structures. Future chemical biology coupled with proteomic approaches could be employed to develop variant specific, complex specific, and pathway specific inhibitors or activators for AAA ATPase proteins.

Topics: ATPases Associated with Diverse Cellular Activities; Binding Sites; Carbazoles; Humans; Molecular Dynamics Simulation; Neoplasms; Pyrazoles; Pyrimidines; Quinazolines; Small Molecule Libraries; Zearalenone

Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.

Topics: Animals; Benzylamines; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Therapy, Combination; Feedback, Physiological; Female; Forkhead Transcription Factors; Gefitinib; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Nude; Models, Biological; Multiprotein Complexes; Neoplasms; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Protein Kinase Inhibitors; Proteins; Proto-Oncogene Proteins c-akt; Quinazolines; Quinoxalines; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-2; Receptor, ErbB-3; Receptor, IGF Type 1; Receptor, Insulin; RNA, Small Interfering; Signal Transduction; TOR Serine-Threonine Kinases; Up-Regulation; Xenograft Model Antitumor Assays

This study was to evaluate the enhancement value of chloroquine (CQ) in cancer cell killing when used in combination with Akt inhibitors. The results showed that the combination of CQ and Akt inhibitors is much more effective than either one alone. Importantly, the CQ-mediated chemosensitization of cell killing effects by Akt inhibitors is cancer specific. In particular, when combined with 10 microM CQ, 1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one (an Akt1 and 2 inhibitor; compound 8) killed cancer cells 10-120 times more effectively than normal cells. Thus, CQ is a very effective and cancer-specific chemosensitizer when used in combination with Akt inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Chloroquine; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Molecular Structure; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinoxalines; Stereoisomerism; Structure-Activity Relationship

Although Akt is known as a survival kinase, inhibitors of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway do not always induce substantial apoptosis. We show that silencing Akt1 alone, or any combination of Akt isoforms, can suppress the growth of tumors established from phosphatase and tensin homologue-null human cancer cells. Although these findings indicate that Akt is essential for tumor maintenance, most tumors eventually rebound. Akt knockdown or inactivation with small molecule inhibitors did not induce significant apoptosis but rather markedly increased autophagy. Further treatment with the lysosomotropic agent chloroquine caused accumulation of abnormal autophagolysosomes and reactive oxygen species, leading to accelerated cell death in vitro and complete tumor remission in vivo. Cell death was also promoted when Akt inhibition was combined with the vacuolar H(+)-adenosine triphosphatase inhibitor bafilomycin A1 or with cathepsin inhibition. These results suggest that blocking lysosomal degradation can be detrimental to cancer cell survival when autophagy is activated, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PI3K-Akt pathway inhibition.

Topics: Animals; Apoptosis; Autophagy; Autophagy-Related Protein 7; Benzylamines; Cell Cycle; Cell Line, Tumor; Chloroquine; Drug Interactions; Female; Furans; Humans; Lysosomes; Macrolides; Mice; Mice, Nude; Mitochondria; Mutation; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proton-Translocating ATPases; PTEN Phosphohydrolase; Pyridines; Pyrimidines; Quinoxalines; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Ubiquitin-Activating Enzymes; Xenograft Model Antitumor Assays