Integrated Drug Expression Analysis for Leukemia

An integrated in silico and ex vivo approach to drug discovery

Drug (Concentration)
[1], [2], etc.
indicates duplication
Cox regression P-value Enriched Pathway Enriched GO
Li Valk Verhaak Willm
Amitriptyline (1.28E-5)
[PubChem]
9.8E-3 8.2E-1 7.7E-1 6.3E-1 hsa05202 Transcriptional misregulation in cancer (2.9E-3)
hsa05203 Viral carcinogenesis (8.3E-3)
Bemegride (2.58E-5)
[PubChem]
3.8E-3 7.7E-2 6.3E-1 2.3E-1 hsa04650 Natural killer cell mediated cytotoxicity (6.1E-4)
hsa04015 Rap1 signaling pathway (6.1E-4)
hsa04014 Ras signaling pathway (1.3E-3)
hsa04360 Axon guidance (6.1E-3)
hsa05223 Non-small cell lung cancer (7.0E-3)
hsa04730 Long-term depression (9.3E-3)
Bisoprolol (9.0E-6)
[PubChem]
9.3E-3 1.6E-1 9.3E-1 8.0E-1 hsa04630 Jak-STAT signaling pathway (7.7E-3)
hsa05020 Prion diseases (7.9E-3)
hsa00100 Steroid biosynthesis (9.3E-3)
GO:0000790 nuclear chromatin (5.3E-5)
GO:0000785 chromatin (5.6E-5)
Chloramphenicol (1.24E-5)
[PubChem]
2.1E-3 8.5E-1 8.9E-1 9.4E-1 hsa04014 Ras signaling pathway (1.6E-3)
hsa04066 HIF-1 signaling pathway (2.0E-3)
hsa05200 Pathways in cancer (3.0E-3)
hsa00591 Linoleic acid metabolism (3.6E-3)
hsa04015 Rap1 signaling pathway (7.1E-3)
GO:0006362 transcription elongation from RNA polymerase I promoter (2.9E-5)
GO:0006363 termination of RNA polymerase I transcription (4.9E-5)
GO:0006360 transcription from RNA polymerase I promoter (9.8E-5)
GO:0006361 transcription initiation from RNA polymerase I promoter (9.8E-5)
Chlorpromazine (1.0E-6)
[PubChem]
8.2E-3 1.6E-1 5.8E-1 3.0E-1 hsa04640 Hematopoietic cell lineage (3.6E-3)
hsa04270 Vascular smooth muscle contraction (6.2E-3)
GO:0046625 sphingolipid binding (7.6E-5)
Coralyne (9.6E-6)
[PubChem]
8.8E-3 1.7E-1 8.6E-1 1.4E-1 hsa04120 Ubiquitin mediated proteolysis (1.7E-3)
hsa00061 Fatty acid biosynthesis (3.4E-3)
hsa04210 Apoptosis (4.7E-3)
GO:0060337 type I interferon-mediated signaling pathway (6.1E-5)
GO:0071357 cellular response to type I interferon (6.1E-5)
GO:0034340 response to type I interferon (6.8E-5)
Diethylcarbamazine (1.02E-5)
[PubChem]
3.0E-3 4.9E-1 5.5E-2 4.5E-2 GO:1901137 carbohydrate derivative biosynthetic process (8.3E-6)
GO:0009101 glycoprotein biosynthetic process (2.5E-5)
GO:0030166 proteoglycan biosynthetic process (6.4E-5)
Felbinac (1.88E-5)
[PubChem]
4.0E-3 5.6E-1 2.0E-1 2.9E-1 hsa04014 Ras signaling pathway (1.7E-3)
hsa00760 Nicotinate and nicotinamide metabolism (3.2E-3)
hsa00120 Primary bile acid biosynthesis (5.9E-3)
Fluorocurarine (1.16E-5)
[PubChem]
2.2E-3 7.5E-1 1.6E-1 7.1E-1 hsa04020 Calcium signaling pathway (8.9E-4)
hsa04022 cGMP-PKG signaling pathway (1.6E-3)
hsa05203 Viral carcinogenesis (2.8E-3)
hsa05034 Alcoholism (2.9E-3)
hsa05322 Systemic lupus erythematosus (4.1E-3)
hsa04024 cAMP signaling pathway (6.4E-3)
hsa04630 Jak-STAT signaling pathway (9.9E-3)
Fulvestrant (1.0E-6)
[PubChem]
1.4E-3 6.6E-2 8.2E-1 6.5E-1 hsa04970 Salivary secretion (7.5E-4)
hsa05032 Morphine addiction (9.4E-4)
hsa04060 Cytokine-cytokine receptor interaction (1.9E-3)
hsa04062 Chemokine signaling pathway (2.8E-3)
hsa04630 Jak-STAT signaling pathway (7.1E-3)
Isoxicam (1.2E-5)
[PubChem]
7.2E-3 9.4E-1 2.3E-1 5.2E-1 hsa04640 Hematopoietic cell lineage (1.6E-3)
hsa04060 Cytokine-cytokine receptor interaction (6.3E-3)
hsa00900 Terpenoid backbone biosynthesis (9.0E-3)
hsa05152 Tuberculosis (9.2E-3)
Liothyronine (6.2E-6)
[PubChem]
2.6E-3 5.0E-2 4.3E-1 2.6E-1 hsa04640 Hematopoietic cell lineage (4.8E-3)
hsa04970 Salivary secretion (5.8E-3)
Nadolol (1.3E-5)
[PubChem]
7.7E-3 5.4E-1 5.6E-1 5.9E-1 hsa04660 T cell receptor signaling pathway (3.7E-3)
hsa05222 Small cell lung cancer (4.8E-3)
hsa04210 Apoptosis (4.8E-3)
hsa05215 Prostate cancer (5.8E-3)
hsa04115 p53 signaling pathway (6.1E-3)
hsa04662 B cell receptor signaling pathway (8.0E-3)
hsa05200 Pathways in cancer (8.1E-3)
hsa05220 Chronic myeloid leukemia (8.5E-3)
hsa00770 Pantothenate and CoA biosynthesis (8.9E-3)
hsa05133 Pertussis (9.7E-3)
Nordihydroguaiaretic Acid (1.0E-6)
[PubChem]
2.3E-3 9.2E-1 8.2E-1 2.0E-1 hsa04080 Neuroactive ligand-receptor interaction (4.4E-3)
hsa00520 Amino sugar and nucleotide sugar metabolism (4.7E-3)
hsa04918 Thyroid hormone synthesis (6.1E-3)
hsa04340 Hedgehog signaling pathway (6.7E-3)
hsa05020 Prion diseases (9.1E-3)
Pentamidine (6.8E-6)
[PubChem]
1.9E-5 4.4E-2 4.9E-1 8.4E-1 hsa05164 Influenza A (6.5E-3)
hsa05162 Measles (8.3E-3)
hsa04921 Oxytocin signaling pathway (8.6E-3)
hsa00120 Primary bile acid biosynthesis (9.1E-3)
GO:0017046 peptide hormone binding (7.5E-5)
GO:0071294 cellular response to zinc ion (7.9E-5)
Prestwick-967 (2.58E-5)
[PubChem]
1.7E-3 3.0E-1 1.3E-1 2.6E-2 hsa04340 Hedgehog signaling pathway (5.4E-3)
hsa05100 Bacterial invasion of epithelial cells (6.6E-3)
Pyrithyldione (2.4E-5)
[PubChem]
2.3E-3 3.3E-2 2.6E-1 2.6E-1 hsa04630 Jak-STAT signaling pathway (2.7E-4)
hsa05414 Dilated cardiomyopathy (2.1E-3)
hsa00770 Pantothenate and CoA biosynthesis (5.2E-3)
hsa05020 Prion diseases (5.5E-3)
hsa05222 Small cell lung cancer (7.4E-3)
Retrorsine (1.14E-5)
[PubChem]
6.0E-5 1.2E-1 7.5E-1 2.2E-1 hsa04060 Cytokine-cytokine receptor interaction (5.9E-3)
GO:0046928 regulation of neurotransmitter secretion (1.0E-5)
GO:0006094 gluconeogenesis (2.2E-5)
GO:0019319 hexose biosynthetic process (3.9E-5)
GO:0051588 regulation of neurotransmitter transport (6.3E-5)
GO:0046364 monosaccharide biosynthetic process (6.8E-5)
Roxithromycin (4.8E-6)
[PubChem]
9.6E-3 9.3E-1 5.5E-1 3.7E-2 hsa04060 Cytokine-cytokine receptor interaction (2.6E-4)
hsa04630 Jak-STAT signaling pathway (7.0E-4)
hsa05200 Pathways in cancer (3.2E-3)
hsa04062 Chemokine signaling pathway (3.3E-3)
hsa04910 Insulin signaling pathway (4.0E-3)
hsa04917 Prolactin signaling pathway (5.3E-3)
hsa05166 HTLV-I infection (5.5E-3)
hsa05223 Non-small cell lung cancer (8.0E-3)
hsa05142 Chagas disease (American trypanosomiasis) (8.5E-3)
hsa04380 Osteoclast differentiation (8.9E-3)
GO:0007611 learning or memory (2.1E-5)
GO:0007612 learning (2.1E-5)
GO:0050890 cognition (4.9E-5)
Salsolidin (1.64E-5)
[PubChem]
9.6E-4 5.5E-1 9.2E-1 6.9E-1 hsa05032 Morphine addiction (3.6E-3)
hsa04662 B cell receptor signaling pathway (4.2E-3)
Sirolimus (1.0E-7)
[PubChem]
3.6E-3 9.8E-1 2.0E-1 6.2E-1 hsa05322 Systemic lupus erythematosus (2.6E-3)
hsa04380 Osteoclast differentiation (7.3E-3)
hsa05416 Viral myocarditis (9.3E-3)
Sulfabenzamide (1.44E-5)
[PubChem]
6.5E-3 3.6E-1 7.6E-1 6.8E-1 hsa00120 Primary bile acid biosynthesis (4.3E-4)
hsa04010 MAPK signaling pathway (5.2E-4)
hsa04015 Rap1 signaling pathway (7.4E-4)
hsa04022 cGMP-PKG signaling pathway (3.7E-3)
hsa05218 Melanoma (4.6E-3)
hsa04020 Calcium signaling pathway (6.3E-3)
Suprofen (1.54E-5)
[PubChem]
6.9E-3 1.1E-1 8.9E-1 9.3E-2 hsa00100 Steroid biosynthesis (9.3E-3)
hsa04151 PI3K-Akt signaling pathway (9.9E-3)
GO:0030334 regulation of cell migration (1.7E-5)
GO:2000145 regulation of cell motility (3.7E-5)
GO:0042627 chylomicron (7.1E-5)
GO:0030335 positive regulation of cell migration (7.8E-5)
GO:0051270 regulation of cellular component movement (8.9E-5)
GO:2000147 positive regulation of cell motility (9.6E-5)
GO:0040012 regulation of locomotion (9.8E-5)
Terguride (8.8E-6)
[PubChem]
7.0E-4 7.5E-1 3.6E-1 9.7E-1 hsa05322 Systemic lupus erythematosus (3.3E-3)
hsa00532 Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (9.5E-3)
GO:0034214 protein hexamerization (7.6E-5)
Trichostatin A (1.0E-7) [1]
[PubChem]
4.9E-3 5.7E-3 2.7E-5 1.7E-1 hsa04721 Synaptic vesicle cycle (7.7E-4)
hsa05120 Epithelial cell signaling in Helicobacter pylori infection (5.9E-3)
hsa05323 Rheumatoid arthritis (6.4E-3)
GO:0034470 ncRNA processing (1.0E-6)
GO:0006364 rRNA processing (1.7E-6)
GO:0016072 rRNA metabolic process (3.1E-6)
GO:0034660 ncRNA metabolic process (3.1E-5)
Trichostatin A (1.0E-7) [2]
[PubChem]
8.7E-3 3.4E-3 2.0E-2 5.2E-1 hsa00520 Amino sugar and nucleotide sugar metabolism (6.4E-3)
hsa00450 Selenocompound metabolism (7.9E-3)
hsa04978 Mineral absorption (8.3E-3)
GO:0006790 sulfur compound metabolic process (1.5E-5)
Trichostatin A (1.0E-7) [3]
[PubChem]
1.7E-4 6.4E-4 2.0E-4 3.1E-1 hsa00790 Folate biosynthesis (3.3E-3)
hsa04913 Ovarian steroidogenesis (5.4E-3)
GO:0006520 cellular amino acid metabolic process (2.4E-5)
GO:0034660 ncRNA metabolic process (3.2E-5)
GO:0006364 rRNA processing (6.3E-5)
GO:0034470 ncRNA processing (8.1E-5)
Trichostatin A (1.0E-7) [4]
[PubChem]
7.5E-4 3.7E-3 1.2E-5 1.1E-1 hsa04066 HIF-1 signaling pathway (1.9E-4)
hsa05230 Central carbon metabolism in cancer (2.0E-4)
hsa05221 Acute myeloid leukemia (4.3E-4)
hsa04110 Cell cycle (8.5E-4)
hsa04151 PI3K-Akt signaling pathway (1.9E-3)
hsa04910 Insulin signaling pathway (2.1E-3)
hsa04914 Progesterone-mediated oocyte maturation (5.5E-3)
hsa05215 Prostate cancer (5.8E-3)
hsa05218 Melanoma (7.5E-3)
hsa00051 Fructose and mannose metabolism (8.1E-3)
hsa05220 Chronic myeloid leukemia (8.5E-3)
hsa05161 Hepatitis B (9.2E-3)
hsa04721 Synaptic vesicle cycle (9.5E-4)
hsa05134 Legionellosis (2.4E-3)
hsa00533 Glycosaminoglycan biosynthesis - keratan sulfate (5.7E-3)
hsa05323 Rheumatoid arthritis (7.7E-3)
GO:0042625 ATPase activity, coupled to transmembrane movement of ions (1.3E-5)
GO:0032391 photoreceptor connecting cilium (1.6E-5)
GO:0044419 interspecies interaction between organisms (3.5E-5)
GO:0000280 nuclear division (4.3E-5)
GO:0007067 mitosis (4.3E-5)
GO:0016747 transferase activity, transferring acyl groups other than amino-acyl groups (9.6E-5)
Trichostatin A (1.0E-7) [5]
[PubChem]
3.5E-4 1.6E-4 4.2E-5 2.7E-2 hsa04721 Synaptic vesicle cycle (2.9E-3)
hsa05110 Vibrio cholerae infection (7.2E-3)
hsa04350 TGF-beta signaling pathway (9.3E-3)
GO:0006221 pyrimidine nucleotide biosynthetic process (3.2E-5)
GO:2001280 positive regulation of unsaturated fatty acid biosynthetic process (9.0E-5)
GO:0031394 positive regulation of prostaglandin biosynthetic process (9.0E-5)
Trichostatin A (1.0E-7) [6]
[PubChem]
1.8E-3 3.4E-2 3.9E-5 1.8E-1 hsa03008 Ribosome biogenesis in eukaryotes (9.8E-5)
hsa05140 Leishmaniasis (7.5E-4)
hsa05168 Herpes simplex infection (4.0E-3)
hsa03013 RNA transport (5.9E-3)
hsa05120 Epithelial cell signaling in Helicobacter pylori infection (9.3E-3)
hsa00450 Selenocompound metabolism (9.7E-3)
hsa05166 HTLV-I infection (9.9E-3)
hsa00790 Folate biosynthesis (3.5E-3)
GO:0007080 mitotic metaphase plate congression (5.7E-5)
GO:0050658 RNA transport (8.0E-5)
GO:0050657 nucleic acid transport (8.0E-5)
GO:0051236 establishment of RNA localization (8.0E-5)
GO:0006405 RNA export from nucleus (8.0E-5)
GO:2001280 positive regulation of unsaturated fatty acid biosynthetic process (9.0E-5)
GO:0031394 positive regulation of prostaglandin biosynthetic process (9.0E-5)
GO:0006729 tetrahydrobiopterin biosynthetic process (2.9E-6)
GO:0046146 tetrahydrobiopterin metabolic process (2.9E-6)
GO:0019438 aromatic compound biosynthetic process (3.4E-5)
GO:0000793 condensed chromosome (4.9E-5)
GO:0006790 sulfur compound metabolic process (8.2E-5)
GO:0042559 pteridine-containing compound biosynthetic process (8.3E-5)
GO:0042558 pteridine-containing compound metabolic process (8.6E-5)
Trimethadione (2.8E-5)
[PubChem]
9.4E-3 1.5E-2 4.7E-2 2.3E-1 hsa04610 Complement and coagulation cascades (4.3E-3)
hsa05133 Pertussis (6.4E-3)
GO:0040017 positive regulation of locomotion (2.9E-5)
GO:0030335 positive regulation of cell migration (6.8E-5)
GO:2000147 positive regulation of cell motility (8.3E-5)
Valproic Acid (0.001) [1]
[PubChem]
7.0E-3 7.6E-4 4.6E-5 1.8E-2 hsa03008 Ribosome biogenesis in eukaryotes (1.0E-3)
hsa05130 Pathogenic Escherichia coli infection (1.8E-3)
hsa05221 Acute myeloid leukemia (2.2E-3)
hsa00051 Fructose and mannose metabolism (7.4E-3)
hsa04060 Cytokine-cytokine receptor interaction (5.2E-3)
hsa05323 Rheumatoid arthritis (6.6E-3)
GO:0044419 interspecies interaction between organisms (9.6E-7)
GO:0051130 positive regulation of cellular component organization (9.0E-6)
GO:0006325 chromatin organization (4.9E-5)
GO:0031346 positive regulation of cell projection organization (6.7E-5)
GO:0010976 positive regulation of neuron projection development (1.0E-4)
GO:0050900 leukocyte migration (1.2E-5)
GO:0044272 sulfur compound biosynthetic process (1.3E-5)
GO:0030201 heparan sulfate proteoglycan metabolic process (3.8E-5)
GO:0006790 sulfur compound metabolic process (8.0E-5)
GO:0015012 heparan sulfate proteoglycan biosynthetic process (8.6E-5)
Valproic Acid (5.0E-4)
[PubChem]
4.8E-4 9.9E-3 3.1E-4 6.7E-2 hsa04721 Synaptic vesicle cycle (1.6E-5)
hsa05120 Epithelial cell signaling in Helicobacter pylori infection (1.1E-3)
hsa05168 Herpes simplex infection (1.6E-3)
hsa05134 Legionellosis (1.9E-3)
GO:0060337 type I interferon-mediated signaling pathway (6.5E-5)
GO:0071357 cellular response to type I interferon (6.5E-5)
GO:0034340 response to type I interferon (7.2E-5)
Valproic Acid (0.001) [2]
[PubChem]
4.3E-3 1.4E-2 3.0E-3 1.2E-2 hsa05120 Epithelial cell signaling in Helicobacter pylori infection (1.4E-3)
hsa04721 Synaptic vesicle cycle (4.7E-3)
hsa05323 Rheumatoid arthritis (7.5E-3)
GO:0042625 ATPase activity, coupled to transmembrane movement of ions (7.5E-5)
GO:0016530 metallochaperone activity (8.8E-5)
Velnacrine (1.22E-5)
[PubChem]
9.9E-3 1.8E-1 7.8E-1 9.2E-1 hsa04071 Sphingolipid signaling pathway (2.8E-3)
hsa05210 Colorectal cancer (4.1E-3)
hsa04668 TNF signaling pathway (5.7E-3)
hsa04068 FoxO signaling pathway (5.7E-3)
hsa04144 Endocytosis (6.3E-3)
hsa04622 RIG-I-like receptor signaling pathway (7.4E-3)
hsa04310 Wnt signaling pathway (7.6E-3)
Wortmannin (1.0E-8)
[PubChem]
4.7E-3 6.0E-1 8.2E-1 6.0E-1 hsa05322 Systemic lupus erythematosus (2.4E-4)
hsa00260 "Glycine, serine and threonine metabolism " (5.7E-4)
hsa05034 Alcoholism (9.1E-4)
hsa04150 mTOR signaling pathway (9.5E-4)
hsa05203 Viral carcinogenesis (1.1E-3)
hsa00970 Aminoacyl-tRNA biosynthesis (1.7E-3)
hsa04964 Proximal tubule bicarbonate reclamation (2.8E-3)
hsa04620 Toll-like receptor signaling pathway (6.8E-3)
hsa05202 Transcriptional misregulation in cancer (7.7E-3)
hsa04380 Osteoclast differentiation (7.7E-3)
hsa05162 Measles (8.9E-3)
hsa00450 Selenocompound metabolism (9.4E-3)
GO:0042326 negative regulation of phosphorylation (4.5E-6)
GO:0045936 negative regulation of phosphate metabolic process (6.1E-6)
GO:0010563 negative regulation of phosphorus metabolic process (6.1E-6)
GO:0009070 serine family amino acid biosynthetic process (6.7E-6)
GO:0006563 L-serine metabolic process (1.2E-5)
GO:0008652 cellular amino acid biosynthetic process (1.8E-5)
GO:0030170 pyridoxal phosphate binding (2.0E-5)
GO:0070279 vitamin B6 binding (2.0E-5)
GO:0006520 cellular amino acid metabolic process (2.2E-5)
GO:0016875 ligase activity, forming carbon-oxygen bonds (3.3E-5)
GO:0004812 aminoacyl-tRNA ligase activity (3.3E-5)
GO:0016876 ligase activity, forming aminoacyl-tRNA and related compounds (3.3E-5)
GO:0015804 neutral amino acid transport (3.6E-5)
GO:0006564 L-serine biosynthetic process (3.6E-5)
GO:0009069 serine family amino acid metabolic process (3.8E-5)
GO:0050865 regulation of cell activation (4.0E-5)
GO:0050900 leukocyte migration (4.4E-5)
GO:0002694 regulation of leukocyte activation (5.0E-5)
GO:0006418 tRNA aminoacylation for protein translation (5.9E-5)
GO:0015175 neutral amino acid transmembrane transporter activity (6.0E-5)
GO:0043039 tRNA aminoacylation (8.7E-5)
GO:0043038 amino acid activation (8.7E-5)
GO:0071900 regulation of protein serine/threonine kinase activity (9.6E-5)

About IDEAL

Screening for drug compounds that exhibit therapeutic properties in the treatment of various disease remain a challenge even after considerable advancement in biomedical research. Here we introduce an integrated platform that exploits gene expression compendia generated from cell-based drug screens and primary tumor tissue to identify therapeutic candidates that can be used in the treatment of acute myeloid leukemia (AML). Our framework further combines these data with patient survival information to identify candidates that presumably have significant impact on AML patient survival. We show that the Drug Regulatory Score (DRS) outputted by our computational approach is highly correlated with in vitro metrics of pharmacological activity. Furthermore, we conducted several in vivo validation experiments of our candidates in AML mouse models to demonstrate the accuracy of our in silico predictions. Finally, we present the construction of a user-friendly database that allows the research community to easily access and implement our framework to generate novel hypotheses. Overall, we present a highly integrated and efficient pre-clinical drug screen framework that can be incorporated into current drug discovery schema.

Research and development laboratories:

 
P value threshold