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1.
Leukemia ; 33(12): 2805-2816, 2019 12.
Article in English | MEDLINE | ID: mdl-31127149

ABSTRACT

Imipridones constitute a novel class of antitumor agents. Here, we report that a second-generation imipridone, ONC212, possesses highly increased antitumor activity compared to the first-generation compound ONC201. In vitro studies using human acute myeloid leukemia (AML) cell lines, primary AML, and normal bone marrow (BM) samples demonstrate that ONC212 exerts prominent apoptogenic effects in AML, but not in normal BM cells, suggesting potential clinical utility. Imipridones putatively engage G protein-coupled receptors (GPCRs) and/or trigger an integrated stress response in hematopoietic tumor cells. Comprehensive GPCR screening identified ONC212 as activator of an orphan GPCR GPR132 and Gαq signaling, which functions as a tumor suppressor. Heterozygous knock-out of GPR132 decreased the antileukemic effects of ONC212. ONC212 induced apoptogenic effects through the induction of an integrated stress response, and reduced MCL-1 expression, a known resistance factor for BCL-2 inhibition by ABT-199. Oral administration of ONC212 inhibited AML growth in vivo and improved overall survival in xenografted mice. Moreover, ONC212 abrogated the engraftment capacity of patient-derived AML cells in an NSG PDX model, suggesting potential eradication of AML initiating cells, and was highly synergistic in combination with ABT-199. Collectively, our results suggest ONC212 as a novel therapeutic agent for AML.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Proteins/genetics , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/metabolism , Receptors, G-Protein-Coupled/genetics , Stress, Physiological , Transcriptional Activation , Animals , Apoptosis/drug effects , Biomarkers , Cell Cycle/drug effects , Cell Cycle Proteins/agonists , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Gene Expression Regulation, Leukemic , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Mice , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/metabolism , Stress, Physiological/genetics , Treatment Outcome , Xenograft Model Antitumor Assays
2.
Clin Cancer Res ; 25(7): 2305-2313, 2019 04 01.
Article in English | MEDLINE | ID: mdl-30559168

ABSTRACT

PURPOSE: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201. EXPERIMENTAL DESIGN: The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. IHC staining of DRD2/DRD5 was performed on tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies. RESULTS: DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a de novo Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from patients with recurrent glioblastoma treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes. CONCLUSIONS: These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.


Subject(s)
Dopamine D2 Receptor Antagonists/pharmacology , Neoplasms/metabolism , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D5/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biomarkers , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance/genetics , Gene Expression , Humans , Imidazoles/pharmacology , Imidazoles/therapeutic use , Immunohistochemistry , Magnetic Resonance Imaging , Neoplasm Grading , Neoplasm Staging , Neoplasms/diagnosis , Neoplasms/drug therapy , Neoplasms/mortality , Prognosis , Protein Binding , Pyridines/pharmacology , Pyridines/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Receptors, Dopamine D2/genetics , Receptors, Dopamine D5/chemistry , Receptors, Dopamine D5/genetics , Signal Transduction
3.
Cell Cycle ; 13(14): 2172-91, 2014.
Article in English | MEDLINE | ID: mdl-24955955

ABSTRACT

Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as "authentic" bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents' gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient's tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off-target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Drug Repositioning , Drug Resistance, Neoplasm/drug effects , Pancreatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Signal Transduction/drug effects , Aniline Compounds/pharmacology , Animals , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Checkpoint Kinase 1 , Cisplatin/pharmacology , DNA Damage , DNA Replication , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Doxorubicin/pharmacology , Humans , Male , Mice, Inbred C57BL , Mice, SCID , Models, Molecular , Nitriles/pharmacology , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/metabolism , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Protein Kinase Inhibitors/chemistry , Protein Kinases/chemistry , Protein Kinases/genetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Quinolines/pharmacology , Time Factors , Xenograft Model Antitumor Assays , Gemcitabine
4.
J Biol Chem ; 288(39): 28068-77, 2013 Sep 27.
Article in English | MEDLINE | ID: mdl-23935097

ABSTRACT

Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here, we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase.


Subject(s)
Gene Expression Regulation , Protein Kinase Inhibitors/chemistry , Receptor, IGF Type 1/metabolism , Receptor, Insulin/metabolism , Adenosine Triphosphate/chemistry , Animals , CHO Cells , Cricetulus , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Humans , MAP Kinase Signaling System , Mutation , Phosphorylation , Protein Conformation , Protein Kinase Inhibitors/classification , Pyrazoles/chemistry , Pyridazines/chemistry
5.
Nat Biotechnol ; 29(11): 1039-45, 2011 Oct 30.
Article in English | MEDLINE | ID: mdl-22037377

ABSTRACT

Small-molecule protein kinase inhibitors are widely used to elucidate cellular signaling pathways and are promising therapeutic agents. Owing to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments that use these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we used functional assays to profile the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases. Quantitative analysis revealed complex and often unexpected interactions between protein kinases and kinase inhibitors, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can identify multitargeted inhibitors of specific, diverse kinases. The results have implications for drug development and provide a resource for selecting compounds to elucidate kinase function and for interpreting the results of experiments involving kinase inhibitors.


Subject(s)
Drug Design , High-Throughput Screening Assays , Protein Kinase Inhibitors/chemistry , Protein Kinases/chemistry , Catalysis , Enzyme Stability , Humans , Protein Binding , Protein Kinase Inhibitors/classification , Protein Kinases/classification , Signal Transduction , Substrate Specificity
6.
Chem Biol ; 15(4): 322-31, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18420139

ABSTRACT

Autoregulatory domains found within kinases may provide more unique targets for chemical inhibitors than the conserved ATP-binding pocket targeted by most inhibitors. The kinase Pak1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. Pak1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation. We developed a screen for allosteric inhibitors targeting Pak1 activation and identified the inhibitor IPA-3. Remarkably, preactivated Pak1 is resistant to IPA-3. IPA-3 also inhibits activation of related Pak isoforms regulated by autoinhibition, but not more distantly related Paks, nor >200 other kinases tested. Pak1 inhibition by IPA-3 in live cells supports a critical role for Pak in PDGF-stimulated Erk activation. These studies illustrate an alternative strategy for kinase inhibition and introduce a highly selective, cell-permeable chemical inhibitor of Pak.


Subject(s)
Drug Evaluation, Preclinical/methods , Homeostasis/drug effects , Protein Kinase Inhibitors/pharmacology , Small Molecule Libraries/pharmacology , p21-Activated Kinases/antagonists & inhibitors , p21-Activated Kinases/metabolism , Animals , Disulfides/chemistry , Disulfides/metabolism , Disulfides/pharmacology , Enzyme Activation/drug effects , Fibroblasts/drug effects , Fibroblasts/metabolism , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Mice , Naphthols/chemistry , Naphthols/metabolism , Naphthols/pharmacology , Platelet-Derived Growth Factor/metabolism , Protein Conformation/drug effects , Protein Kinase Inhibitors/metabolism , Small Molecule Libraries/metabolism , Substrate Specificity
7.
Expert Opin Drug Discov ; 3(6): 607-621, 2008 Jun.
Article in English | MEDLINE | ID: mdl-19662101

ABSTRACT

BACKGROUND: Protein kinases represent one of the most promising groups of drug targets owing to their involvement in such pathological conditions as cancer, inflammatory diseases, neural disorders, and metabolism problems. In the last few years, numerous pharmaceutical and biotech companies have established kinase high-throughput screening (HTS) programs, and the reagent and service industries for kinase assay platforms, kits, and profiling services have begun to thrive. OBJECTIVE: The plethora of different assay formats available today poses a great challenge to scientists who want to select a technology that will be cost efficient, convenient to use, and have low false positive and false negative rates. METHODS: In the current review, we summarize the most commonly used kinase assay methods in the drug discovery process, present the advantages and disadvantages of each of these methods, and discuss the challenges of discovering kinase inhibitors by using these technologies. CONCLUSIONS: The decision of selecting the assay formats for HTS or service platform for profiling should take into account not only the final goals of the screens but also the limitation of resources.

8.
J Biol Chem ; 282(21): 15667-78, 2007 May 25.
Article in English | MEDLINE | ID: mdl-17392278

ABSTRACT

The p21-activated kinases (Paks) serve as effectors of the Rho family GTPases Rac and Cdc42. The six human Paks are divided into two groups based on sequence similarity. Group I Paks (Pak1 to -3) phosphorylate a number of substrates linking this group to regulation of the cytoskeleton and both proliferative and anti-apoptotic signaling. Group II Paks (Pak4 to -6) are thought to play distinct functional roles, yet their few known substrates are also targeted by Group I Paks. To determine if the two groups recognize distinct target sequences, we used a degenerate peptide library method to comprehensively characterize the consensus phosphorylation motifs of Group I and II Paks. We find that Pak1 and Pak2 exhibit virtually identical substrate specificity that is distinct from that of Pak4. Based on structural comparisons and mutagenesis, we identified two key amino acid residues that mediate the distinct specificities of Group I and II Paks and suggest a structural basis for these differences. These results implicate, for the first time, residues from the small lobe of a kinase in substrate selectivity. Finally, we utilized the Pak1 consensus motif to predict a novel Pak1 phosphorylation site in Pix (Pak-interactive exchange factor) and demonstrate that Pak1 phosphorylates this site both in vitro and in cultured cells. Collectively, these results elucidate the specificity of Pak kinases and illustrate a general method for the identification of novel sites phosphorylated by Paks.


Subject(s)
Cell Cycle Proteins/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Protein Processing, Post-Translational/physiology , Protein Serine-Threonine Kinases/metabolism , Amino Acid Motifs/genetics , Cell Cycle Proteins/chemistry , Cell Cycle Proteins/genetics , Cell Line , Guanine Nucleotide Exchange Factors/chemistry , Guanine Nucleotide Exchange Factors/genetics , Humans , Mutagenesis, Site-Directed , Phosphorylation , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Protein Structure, Tertiary/genetics , Rho Guanine Nucleotide Exchange Factors , Structural Homology, Protein , Structure-Activity Relationship , Substrate Specificity , cdc42 GTP-Binding Protein/metabolism , rho GTP-Binding Proteins/metabolism
9.
Structure ; 15(2): 201-13, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17292838

ABSTRACT

p21-activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4-6) regulate a wide variety of cellular functions, and PAK deregulation has been linked to tumor development. Structural comparison of five high-resolution structures comprising all active, monophosphorylated group II catalytic domains revealed a surprising degree of domain plasticity, including a number of catalytically productive and nonproductive conformers. Rearrangements of helix alphaC, a key regulatory element of kinase function, resulted in an additional helical turn at the alphaC N terminus and a distortion of its C terminus, a movement hitherto unseen in protein kinases. The observed structural changes led to the formation of interactions between conserved residues that structurally link the glycine-rich loop, alphaC, and the activation segment and firmly anchor alphaC in an active conformation. Inhibitor screening identified six potent PAK inhibitors from which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5.


Subject(s)
Catalytic Domain , Protein Serine-Threonine Kinases/chemistry , Amino Acid Sequence , Animals , Catalytic Domain/drug effects , Catalytic Domain/genetics , Crystallography , Molecular Sequence Data , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Purines/chemistry
10.
Curr Biol ; 15(5): 459-63, 2005 Mar 08.
Article in English | MEDLINE | ID: mdl-15753041

ABSTRACT

Regulation of intracellular transport plays a role in a number of processes, including mitosis, determination of cell polarity, and neuronal growth. In Xenopus melanophores, transport of melanosomes toward the cell center is triggered by melatonin, whereas their dispersion throughout the cytoplasm is triggered by melanocyte-stimulating hormone (MSH), with both of these processes mediated by cAMP-dependent protein kinase A (PKA) activity [1, 2]. Recently, the ERK (extracellular signal-regulated kinase) pathway has been implicated in regulating organelle transport and signaling downstream of melatonin receptor [3, 4]. Here, we directly demonstrate that melanosome transport is regulated by ERK signaling. Inhibition of ERK signaling by the MEK (MAPK/ERK kinase) inhibitor U0126 blocks bidirectional melanosome transport along microtubules, and stimulation of ERK by constitutively active MEK1/2 stimulates transport. These effects are specific because perturbation of ERK signaling has no effect on the movement of lysosomes, organelles related to melanosomes [5]. Biochemical analysis demonstrates that MEK and ERK are present on melanosomes and transiently activated by melatonin. Furthermore, this activation correlates with an increase in melanosome transport. Finally, direct inhibition of PKA transiently activates ERK, demonstrating that ERK acts downstream of PKA. We propose that signaling of organelle bound ERK is a key pathway that regulates bidirectional, microtubule-based melanosome transport.


Subject(s)
Melanophores/metabolism , Melanosomes/metabolism , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Signal Transduction/drug effects , Xenopus/physiology , Animals , Biological Transport/drug effects , Biological Transport/physiology , Butadienes/pharmacology , Cyclic AMP-Dependent Protein Kinases/metabolism , DNA Primers , Enzyme Inhibitors/pharmacology , Green Fluorescent Proteins , Melanosomes/physiology , Melatonin , Microtubules/metabolism , Mitogen-Activated Protein Kinase Kinases/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Nitriles/pharmacology , Plasmids/genetics , Signal Transduction/physiology , Transfection
11.
J Cell Biol ; 160(3): 297-301, 2003 Feb 03.
Article in English | MEDLINE | ID: mdl-12551954

ABSTRACT

Kinesin II is a heterotrimeric plus end-directed microtubule motor responsible for the anterograde movement of organelles in various cell types. Despite substantial literature concerning the types of organelles that kinesin II transports, the question of how this motor associates with cargo organelles remains unanswered. To address this question, we have used Xenopus laevis melanophores as a model system. Through analysis of kinesin II-mediated melanosome motility, we have determined that the dynactin complex, known as an anchor for cytoplasmic dynein, also links kinesin II to organelles. Biochemical data demonstrates that the putative cargo-binding subunit of Xenopus kinesin II, Xenopus kinesin II-associated protein (XKAP), binds directly to the p150Glued subunit of dynactin. This interaction occurs through aa 530-793 of XKAP and aa 600-811 of p150Glued. These results reveal that dynactin is required for transport activity of microtubule motors of opposite polarity, cytoplasmic dynein and kinesin II, and may provide a new mechanism to coordinate their activities.


Subject(s)
Caenorhabditis elegans Proteins , Calcium-Binding Proteins/metabolism , Melanophores/metabolism , Microtubule-Associated Proteins/metabolism , Muscle Proteins/metabolism , Organelles/metabolism , Protein Transport/physiology , Animals , Binding, Competitive/physiology , Cells, Cultured , Dynactin Complex , Kinesins/metabolism , Macromolecular Substances , Melanosomes/metabolism , Models, Biological , Protein Binding/physiology , Xenopus Proteins , Xenopus laevis
12.
Trends Cell Biol ; 12(1): 21-7, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11854006

ABSTRACT

Eukaryotic cells organize their cytoplasm by moving different organelles and macromolecular complexes along microtubules and actin filaments. These movements are powered by numerous motor proteins that must recognize their respective cargoes in order to function. Recently, several proteins that interact with motors have been identified by yeast two-hybrid and biochemical analyses, and their roles in transport are now being elucidated. In several cases, analysis of the binding partners helped to identify new transport pathways, new types of cargo, and transport regulated at the level of motor-cargo binding. We discuss here how different motors of the kinesin, dynein and myosin families recognize their cargo and how motor-cargo interactions are regulated.


Subject(s)
Carrier Proteins/metabolism , Dyneins/metabolism , Kinesins/metabolism , Membrane Proteins , Myosins/metabolism , rab GTP-Binding Proteins , Animals , Biological Transport, Active/physiology , Blood Proteins/metabolism , Dynactin Complex , Humans , Microtubule-Associated Proteins/metabolism , Molecular Motor Proteins/metabolism , Two-Hybrid System Techniques/trends , rab27 GTP-Binding Proteins
13.
J Cell Biol ; 156(5): 855-65, 2002 Mar 04.
Article in English | MEDLINE | ID: mdl-11864991

ABSTRACT

Many cellular components are transported using a combination of the actin- and microtubule-based transport systems. However, how these two systems work together to allow well-regulated transport is not clearly understood. We investigate this question in the Xenopus melanophore model system, where three motors, kinesin II, cytoplasmic dynein, and myosin V, drive aggregation or dispersion of pigment organelles called melanosomes. During dispersion, myosin V functions as a "molecular ratchet" to increase outward transport by selectively terminating dynein-driven minus end runs. We show that there is a continual tug-of-war between the actin and microtubule transport systems, but the microtubule motors kinesin II and dynein are likely coordinated. Finally, we find that the transition from dispersion to aggregation increases dynein-mediated motion, decreases myosin V--mediated motion, and does not change kinesin II--dependent motion. Down-regulation of myosin V contributes to aggregation by impairing its ability to effectively compete with movement along microtubules.


Subject(s)
Actin Cytoskeleton/metabolism , Melanophores/metabolism , Microtubules/metabolism , Molecular Motor Proteins/metabolism , Protein Transport/physiology , Xenopus laevis/metabolism , Animals , Calcium-Binding Proteins/metabolism , Cell Line, Transformed , Dyneins/metabolism , Kinesins , Monophenol Monooxygenase/antagonists & inhibitors , Monophenol Monooxygenase/metabolism , Muscle Proteins/metabolism , Myosin Type V/metabolism , Phenylthiourea/pharmacology , Pigments, Biological/metabolism , Xenopus Proteins
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