Repurposing Drugs for Breast Cancer

The BrCa dataset is composed of the activities of compounds assayed on 9 breast cancer cell lines in all ChEMBL DB assays. In this case, for analysis purposes, all cancer data rows have been removed from the master dataset but Breast cancer average potency and flags for each assayed compound have been appended as separate columns to configure class descriptors.

In this section we will use the BrCa experiments stored in the ChEMBL DB to validate a predictive model that allows prediction of BrCa activity for the 1.5M unique molecules with 13M activity records in te DB focusing on molecules that are actually prescription drugs.

About 3k among the 1.5M annotated molecules with activity records in the ChEMBL DB are prescription drugs. For some of them, there is a record of activity on BrCa cell line experiments, but for the most that don’t have any, there is a predicted score. The variable BrCaScore contains the actual score if it exists, but the predicted one if it doesn’t. These scores have a -log(molar potency) scale.

Applying the dashboard based selection methods described in the prediction of BrCa activity section upon prescription drugs we have created unique drug target pairs with average scores per pair: the already described BrCaScore and the chemblScore which shows the effect that the molecule average score for each particular target.

The graph below shows BrCaScore vs chemblScore. Marked dots are displayed on the right side showing the targets where the drugs have an activity record,  and the value, in bars of their potency at target compared to the potency inhibiting BrCa cell lines growth. There is also a 3rd blue bar showing the predicted cytotoxicity from the cytotox prediction section. Left chart is splitted in three boxes, depending on the drugs have indications for breast cancer, any indication for tumor treatment, or lack of any indication for tumoral diseases. For repurposing, we will focus on the 3rd group. Marked dots are those of the highest potency in the two scores.

 

And here, most potent at target and a score >6 for BrCa…

 

Below, most potent at BrCa and a score >6 for each target…

 

Finally, we can look at this treemap showing the clinical phase achieved by the drugs, current indications, published MoAs and colored by their potency inhibiting BrCa cell lines growth.

BrCa is one of the most investigated diseases, so it should not be weird to find literature references that associate some of these drugs toBrCa, as it can be seen in the table below.

drugNamekindOfBrCaScoreRefFofDrugcomment
ANGIOTENSIN IIpredictedEffects of Angiotensin, Vasopressin and Aldosterone on Proliferation …
ATOSIBANpredictedThe Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a …
AZITHROMYCINpredictedAntibiotics target MCF-7 breast cancer stem cells in hypoxic …
BATEFENTEROLpredictednoRefFound
CLARITHROMYCINpredictedRepurposing Drugs in Oncology (ReDO)—clarithromycin as an anti …
DAUNORUBICIN HYDROCHLORIDEpredictedDaunorubicin – Breastcancer.orgleukemia and sarcoma
DIGITOXINactualEvaluating the Cancer Therapeutic Potential of Cardiac Glycosides
EDOXABANpredictedLate-stage Products – R&D – Daiichi Sankyo
FLUTICASONE PROPIONATEpredictedIncreases risk of breast Cancer!
IB-MECApredictedAn adenosine analogue, IB-MECA, down-regulates estrogen … – NCBI
LANATOSIDE CactualLanatoside C, a cardiac glycoside, acts through protein kinase Cδ to …
MACITENTANpredictedTreatment of experimental human breast cancer and lung … – NCBI – NIH
METILDIGOXINpredictednoRefFound
MORICIZINEpredictednoRefFound
PODOFILOXactualnoRefFound
SIMEPREVIRpredictedDrug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir.as BRCP inhibitor
TACROLIMUSpredictedThe Calcineurin Inhibitor Tacrolimus Inhibits Breast Tumor Growth In …
ULIMORELINpredictednoRefFound
VASOPRESSINpredictedEffects of Angiotensin, Vasopressin and Aldosterone on Proliferation …

Even more interesting, the drugs have activity records for several targets, and mos of them count with literature references that associate them to BrCa.

drugNamereportedMoAschemblProteinNameRefLinkchemblProteinScoreActualOrPredictedBrCaScorekindOfBrCaScoreCytotoxCombinedPrediction
FLUTICASONE PROPIONATEGlucocorticoid receptor agonistGlucocorticoid receptorTargeting the glucocorticoid receptor in breast and prostate cancers …8.8493764565.4112375predicted5.042538366
IB-MECAAdenosine A3 receptor agonistAdenosine A1 receptorThe effect of adenosine A1 receptor agonist and antagonist on p53 …7.473755.851600576predicted4.586526533
IB-MECAAdenosine A3 receptor agonistAdenosine A3 receptor Chung H, et al. The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor-positive and estrogen receptor-negative human breast cancers. Mol. Cancer. Ther. 2006;5:685–692. [PubMed]8.3003828845.851600576predicted4.586526533
ATOSIBANOxytocin receptor antagonistDNA-(apurinic or apyrimidinic site) lyaseExtreme Expression of DNA Repair Protein Apurinic/Apyrimidinic …7.6989700045.885625predicted3.904320422
ATOSIBANOxytocin receptor antagonistOxytocin receptorThe Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a …7.4785.885625predicted3.904320422
ATOSIBANOxytocin receptor antagonistVasopressin V1a receptorEffects of Angiotensin, Vasopressin and Aldosterone on Proliferation …9.1166666675.885625predicted3.904320422
ATOSIBANOxytocin receptor antagonistVasopressin V1b receptorEffects of Angiotensin, Vasopressin and Aldosterone on Proliferation …7.365.885625predicted3.904320422
MACITENTANEndothelin receptor, ET-A/ET-B antagonistEndothelin receptor ET-ATreatment of experimental human breast cancer and lung … – NCBI – NIH9.35.923261161predicted6.857279006
EDOXABANCoagulation factor XFormation of tissue factor-factor VIIa-factor Xa complex prevents apoptosis in human breast cancer cells.9.256.112388393predicted4.170271366
ANGIOTENSIN IIAngiotensin II receptor agonistAngiotensin II receptorAngiotensin II Facilitates Breast Cancer Cell Migration and Metastasis8.9068181826.131783765predicted5.400161733
TACROLIMUSFK506-binding protein 1A inhibitor/Calcineurin inhibitorFK506-binding protein 1AThe Calcineurin Inhibitor Tacrolimus Inhibits Breast Tumor Growth In …8.7271428576.175169643predicted4.513259152
TACROLIMUSFK506-binding protein 1A inhibitor/Calcineurin inhibitorFK506-binding protein 1BThe Calcineurin Inhibitor Tacrolimus Inhibits Breast Tumor Growth In …9.46.175169643predicted4.513259152
TACROLIMUSFK506-binding protein 1A inhibitor/Calcineurin inhibitorPeptidyl-prolyl cis-trans isomerase FKBP5The role of FKBP5 in cancer aetiology and chemoresistance7.16.175169643predicted4.513259152
TACROLIMUSFK506-binding protein 1A inhibitor/Calcineurin inhibitorSerine/threonine-protein kinase mTORNew targets for therapy in breast cancer: mammalian target of rapamycin8.766.175169643predicted4.513259152
BATEFENTEROLBeta-2 adrenergic receptor agonist, Muscarinic acetylcholine receptor M2 antagonist, Muscarinic acetylcholine receptor M3 antagonistBeta-2 adrenergic receptorβ 2 -Adrenergic Receptor Agonists Inhibit the Proliferation of 1321N1 …9.66.237205357predicted4.819267444
BATEFENTEROLBeta-2 adrenergic receptor agonist, Muscarinic acetylcholine receptor M2 antagonist, Muscarinic acetylcholine receptor M3 antagonistMuscarinic acetylcholine receptor M3Muscarinic Receptor Agonists and Antagonists: Effects on Cancer8.76.237205357predicted4.819267444
VASOPRESSINVasopressin receptor agonistOxytocin receptorThe Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a …7.2499086086.795507674predicted5.450990369
VASOPRESSINVasopressin receptor agonistPeripheral myelin protein 22Identification of molecular markers for metastasis-related genes in …7.1924649726.795507674predicted5.450990369
VASOPRESSINVasopressin receptor agonistVasopressin V1a receptorEffects of Angiotensin, Vasopressin and Aldosterone on Proliferation …8.86046.795507674predicted5.450990369
VASOPRESSINVasopressin receptor agonistVasopressin V1b receptorEffects of Angiotensin, Vasopressin and Aldosterone on Proliferation …8.802019446.795507674predicted5.450990369
VASOPRESSINVasopressin receptor agonistVasopressin V2 receptorEffects of Angiotensin, Vasopressin and Aldosterone on Proliferation …9.2087465736.795507674predicted5.450990369
DAUNORUBICIN HYDROCHLORIDEDNA inhibitor, DNA topoisomerase II alpha inhibitorIsocitrate dehydrogenase [NADP] cytoplasmicHuman DNA topoisomerase II-alpha: A new … – ScienceDirect.com7.1360826236.881199616predicted3.424770902
LANATOSIDE CGemininSpotlight on Geminin | Breast Cancer Research | Full Text6.2361746377.08825actual5.444662098
LANATOSIDE CMothers against decapentaplegic homolog 3Mothers against decapentaplegic homolog 3 – Wikipedia5.8500115447.08825actual5.444662098
LANATOSIDE CNuclear factor erythroid 2-related factor 2Perspectives of the Nrf-2 signaling pathway in cancer progression and …6.7861353767.08825actual5.444662098
LANATOSIDE CNuclear receptor ROR-gammaNuclear Receptor ROR Gamma Market: Production, Revenue, Industry …5.157.08825actual5.444662098
ULIMORELINGhrelin agonistGhrelin receptorGhrelin receptor agonists as novel breast cancer therapeutics – Figshare7.577.1380625predicted6.961990852
DIGITOXINSodium/potassium-transporting ATPase inhibitorAndrogen ReceptorTargeting the Androgen Receptor in Breast Cancer – The ASCO Post5.9618239197.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorATPase family AAA domain-containing protein 5Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related …6.8362424767.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorBile acid receptor FXRThe farnesoid X receptor is expressed in breast cancer and regulates …6.3499840487.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorCellular tumor antigen p53The Role of the p53 Tumour Suppressor Gene in Human Breast Cancer7.57.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorDNA topoisomerase II betaTopoisomerases II alpha and beta as therapy targets in breast cancer …57.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorGemininSpotlight on Geminin | Breast Cancer Research | Full Text6.7556890897.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorIsocitrate dehydrogenase [NADP] cytoplasmicIsocitrate dehydrogenases in physiology and cancer: biochemical and …6.686132787.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorMicrotubule-associated protein tauMicrotubule-associated protein tau: A marker of paclitaxel … – NCBI – NIH57.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorMothers against decapentaplegic homolog 3Mothers against decapentaplegic homolog 3 – Wikipedia5.9000087667.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorNuclear factor erythroid 2-related factor 2Perspectives of the Nrf-2 signaling pathway in cancer progression and …6.7587470497.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorNuclear factor NF-kappa-B p105 subunitNF-kappa B genes have a major role in Inflammatory Breast Cancer …7.4888353127.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorPeripheral myelin protein 22Identification of molecular markers for metastasis-related genes in …4.9921882347.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorPeroxisome proliferator-activated receptor deltaA novel peroxisome proliferator-activated receptor delta … – NCBI6.5714895097.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorPeroxisome proliferator-activated receptor gammaThe role of peroxisome proliferator-activated receptor-γ in breast cancer.6.5000381347.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorPrelamin-A/CThe clinicopathological significance of lamin A/C, lamin B1 and lamin …6.057.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorProto-oncogene c-JUNc-Jun Induces Mammary Epithelial Cellular Invasion and Breast …6.6642215657.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorRetinoid X receptor alphaA retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha …7.625039137.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorSerum albuminSerum albumin as a modulator on growth of the human breast cancer …6.4534982097.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorSignal transducer and activator of transcription 3Signal transducer and activator of transcription-3 and breast cancer …6.157.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorSodium/potassium-transporting ATPaseSodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related …8.17.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorSolute carrier organic anion transporter family member 1B1Tumor-Specific Expression of Organic Anion-Transporting – Hindawi5.1132495467.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorSolute carrier organic anion transporter family member 1B3Tumor-Specific Expression of Organic Anion-Transporting – Hindawi5.3045396757.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorSolute carrier organic anion transporter family member 4C1Tumor-Specific Expression of Organic Anion-Transporting – Hindawi6.927.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorThyroid hormone receptor beta-1Targeting Thyroid Hormone Receptor Beta in Triple Negative Breast …7.1499667427.398125actual4.314638489
DIGITOXINSodium/potassium-transporting ATPase inhibitorVitamin D receptorVitamin D receptor as a target for breast cancer therapy. – NCBI6.2500319167.398125actual4.314638489
SIMEPREVIRNS3/4A Protease InhibitorCathepsin SCathepsin S Mediates Brain-Specific Breast Cancer Metastasis …6.17.40790625predicted4.549179982
MORICIZINEGlucagon-like peptide 1 receptorGlucagon-like peptide-1 receptor agonists and risk of breast cancer.5.0999990357.481649319predicted3.501628141
MORICIZINEHistone acetyltransferase GCN5Histone acetyltransferase inhibitors block neuroblastoma cell growth …6.70005717.481649319predicted3.501628141
MORICIZINEHistone-lysine N-methyltransferase, H3 lysine-9 specific 3Histone lysine methyltransferases as anti-cancer targets for drug …6.0499760937.481649319predicted3.501628141
MORICIZINEHypoxia-inducible factor 1 alphaHypoxia-inducible factor 1 and breast cancer metastasis – NCBI – NIH5.87.481649319predicted3.501628141
MORICIZINEPeripheral myelin protein 22Identification of molecular markers for metastasis-related genes in …7.0604807477.481649319predicted3.501628141
MORICIZINEPrelamin-A/CThe clinicopathological significance of lamin A/C, lamin B1 and lamin …9.3979400097.481649319predicted3.501628141
PODOFILOXUnknownAndrogen ReceptorTargeting the Androgen Receptor in Breast Cancer – The ASCO Post5.4130588587.967625actual5.031382053
PODOFILOXUnknownATPase family AAA domain-containing protein 5ATAD5 ATPase family, AAA domain containing 5 [ (human)] – NCBI7.0362121737.967625actual5.031382053
PODOFILOXUnknownCytochrome P450 2C19CYP2C19*17 is associated with decreased breast cancer risk. – NCBI5.37.967625actual5.031382053
PODOFILOXUnknownCytochrome P450 2C9Tamoxifen inhibits cytochrome P450 2C9 activity: A possible …5.47.967625actual5.031382053
PODOFILOXUnknownDNA-(apurinic or apyrimidinic site) lyaseExtreme Expression of DNA Repair Protein Apurinic/Apyrimidinic …5.9500071437.967625actual5.031382053
PODOFILOXUnknownGemininSpotlight on Geminin | Breast Cancer Research | Full Text7.8162724257.967625actual5.031382053
PODOFILOXUnknownHypoxia-inducible factor 1 alphaHypoxia-inducible factor 1 and breast cancer metastasis – NCBI – NIH7.87.967625actual5.031382053
PODOFILOXUnknownIsocitrate dehydrogenase [NADP] cytoplasmicIsocitrate dehydrogenases in physiology and cancer: biochemical and …6.686132787.967625actual5.031382053
PODOFILOXUnknownNuclear factor erythroid 2-related factor 2Perspectives of the Nrf-2 signaling pathway in cancer progression and …6.2158963497.967625actual5.031382053
PODOFILOXUnknownNuclear receptor subfamily 0 group B member 1noRefFound5.677.967625actual5.031382053
PODOFILOXUnknownPeripheral myelin protein 22Identification of molecular markers for metastasis-related genes in …7.7712710067.967625actual5.031382053
PODOFILOXUnknownPeroxisome proliferator-activated receptor deltaA novel peroxisome proliferator-activated receptor delta … – NCBI7.0922469887.967625actual5.031382053
PODOFILOXUnknownPrelamin-A/CThe clinicopathological significance of lamin A/C, lamin B1 and lamin …7.5257.967625actual5.031382053
PODOFILOXUnknownProto-oncogene c-JUNc-Jun activation is associated with proliferation and angiogenesis in …6.840753387.967625actual5.031382053
PODOFILOXUnknownSolute carrier organic anion transporter family member 1B1Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related …5.2474606937.967625actual5.031382053
PODOFILOXUnknownSolute carrier organic anion transporter family member 1B3noRefFound6.2962226897.967625actual5.031382053
PODOFILOXUnknownTubulinTubulin protein: MCF-7 cancer cell – Cytoskeleton, Inc.5.5026021197.967625actual5.031382053
CLARITHROMYCINBacterial 70S ribosome inhibitorSolute carrier organic anion transporter family member 1B1Lee E, Luo J, Su Y-C, Lewinger JP, Schumacher FR, et al. (2014) Hormone metabolism pathway genes and mammographic density change after quitting estrogen and progestin combined hormone therapy in the California Teachers Study. Breast Cancer Research 16: 477. go to article5.3538936598.242964275predicted4.461185566
CLARITHROMYCINBacterial 70S ribosome inhibitorSolute carrier organic anion transporter family member 1B3Uptake transporter organic anion transporting polypeptide 1B3 … – NCBI5.387068588.242964275predicted4.461185566
AZITHROMYCINBacterial 70S ribosome inhibitorGemininSpotlight on Geminin | Breast Cancer Research | Full Text5.3991292138.247836908predicted4.66093881
AZITHROMYCINBacterial 70S ribosome inhibitorIsocitrate dehydrogenase [NADP] cytoplasmicIsocitrate dehydrogenases in physiology and cancer: biochemical and …5.2362127398.247836908predicted4.66093881
AZITHROMYCINBacterial 70S ribosome inhibitorPrelamin-A/CThe clinicopathological significance of lamin A/C, lamin B1 and lamin …6.28.247836908predicted4.66093881
AZITHROMYCINBacterial 70S ribosome inhibitorRetinoid X receptor alphaA retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha …5.3500034938.247836908predicted4.66093881
AZITHROMYCINBacterial 70S ribosome inhibitorTAR DNA-binding protein 43TARDBP regulates glycolysis in hepatocellular carcinoma by …5.3500034938.247836908predicted4.66093881
AZITHROMYCINBacterial 70S ribosome inhibitorTranscription factor AP-1The AP-1 transcription factor regulates breast cancer cell … – NCBI58.247836908predicted4.66093881
METILDIGOXINAndrogen ReceptorTargeting the Androgen Receptor in Breast Cancer – The ASCO Post6.4982329358.317873512predicted2.885625
CLARITHROMYCINBacterial 70S ribosome inhibitorStreptokinase AAmicoumacin A induces cancer cell death by targeting the … – Nature7.221848758.242964275predicted4.461185566
AZITHROMYCINBacterial 70S ribosome inhibitorStreptokinase AAmicoumacin A induces cancer cell death by targeting the … – Nature7.221848758.247836908predicted4.66093881