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.

drugName kindOfBrCaScore RefFofDrug comment
ANGIOTENSIN II predicted Effects of Angiotensin, Vasopressin and Aldosterone on Proliferation …
ATOSIBAN predicted The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a …
AZITHROMYCIN predicted Antibiotics target MCF-7 breast cancer stem cells in hypoxic …
BATEFENTEROL predicted noRefFound
CLARITHROMYCIN predicted Repurposing Drugs in Oncology (ReDO)—clarithromycin as an anti …
DAUNORUBICIN HYDROCHLORIDE predicted Daunorubicin – Breastcancer.org leukemia and sarcoma
DIGITOXIN actual Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides
EDOXABAN predicted Late-stage Products – R&D – Daiichi Sankyo
FLUTICASONE PROPIONATE predicted Increases risk of breast Cancer!
IB-MECA predicted An adenosine analogue, IB-MECA, down-regulates estrogen … – NCBI
LANATOSIDE C actual Lanatoside C, a cardiac glycoside, acts through protein kinase Cδ to …
MACITENTAN predicted Treatment of experimental human breast cancer and lung … – NCBI – NIH
METILDIGOXIN predicted noRefFound
MORICIZINE predicted noRefFound
PODOFILOX actual noRefFound
SIMEPREVIR predicted Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir. as BRCP inhibitor
TACROLIMUS predicted The Calcineurin Inhibitor Tacrolimus Inhibits Breast Tumor Growth In …
ULIMORELIN predicted noRefFound
VASOPRESSIN predicted Effects 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.

drugName reportedMoAs chemblProteinName RefLink chemblProteinScore ActualOrPredictedBrCaScore kindOfBrCaScore CytotoxCombinedPrediction
FLUTICASONE PROPIONATE Glucocorticoid receptor agonist Glucocorticoid receptor Targeting the glucocorticoid receptor in breast and prostate cancers … 8.849376456 5.4112375 predicted 5.042538366
IB-MECA Adenosine A3 receptor agonist Adenosine A1 receptor The effect of adenosine A1 receptor agonist and antagonist on p53 … 7.47375 5.851600576 predicted 4.586526533
IB-MECA Adenosine A3 receptor agonist Adenosine 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] 8.300382884 5.851600576 predicted 4.586526533
ATOSIBAN Oxytocin receptor antagonist DNA-(apurinic or apyrimidinic site) lyase Extreme Expression of DNA Repair Protein Apurinic/Apyrimidinic … 7.698970004 5.885625 predicted 3.904320422
ATOSIBAN Oxytocin receptor antagonist Oxytocin receptor The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a … 7.478 5.885625 predicted 3.904320422
ATOSIBAN Oxytocin receptor antagonist Vasopressin V1a receptor Effects of Angiotensin, Vasopressin and Aldosterone on Proliferation … 9.116666667 5.885625 predicted 3.904320422
ATOSIBAN Oxytocin receptor antagonist Vasopressin V1b receptor Effects of Angiotensin, Vasopressin and Aldosterone on Proliferation … 7.36 5.885625 predicted 3.904320422
MACITENTAN Endothelin receptor, ET-A/ET-B antagonist Endothelin receptor ET-A Treatment of experimental human breast cancer and lung … – NCBI – NIH 9.3 5.923261161 predicted 6.857279006
EDOXABAN Coagulation factor X Formation of tissue factor-factor VIIa-factor Xa complex prevents apoptosis in human breast cancer cells. 9.25 6.112388393 predicted 4.170271366
ANGIOTENSIN II Angiotensin II receptor agonist Angiotensin II receptor Angiotensin II Facilitates Breast Cancer Cell Migration and Metastasis 8.906818182 6.131783765 predicted 5.400161733
TACROLIMUS FK506-binding protein 1A inhibitor/Calcineurin inhibitor FK506-binding protein 1A The Calcineurin Inhibitor Tacrolimus Inhibits Breast Tumor Growth In … 8.727142857 6.175169643 predicted 4.513259152
TACROLIMUS FK506-binding protein 1A inhibitor/Calcineurin inhibitor FK506-binding protein 1B The Calcineurin Inhibitor Tacrolimus Inhibits Breast Tumor Growth In … 9.4 6.175169643 predicted 4.513259152
TACROLIMUS FK506-binding protein 1A inhibitor/Calcineurin inhibitor Peptidyl-prolyl cis-trans isomerase FKBP5 The role of FKBP5 in cancer aetiology and chemoresistance 7.1 6.175169643 predicted 4.513259152
TACROLIMUS FK506-binding protein 1A inhibitor/Calcineurin inhibitor Serine/threonine-protein kinase mTOR New targets for therapy in breast cancer: mammalian target of rapamycin 8.76 6.175169643 predicted 4.513259152
BATEFENTEROL Beta-2 adrenergic receptor agonist, Muscarinic acetylcholine receptor M2 antagonist, Muscarinic acetylcholine receptor M3 antagonist Beta-2 adrenergic receptor β 2 -Adrenergic Receptor Agonists Inhibit the Proliferation of 1321N1 … 9.6 6.237205357 predicted 4.819267444
BATEFENTEROL Beta-2 adrenergic receptor agonist, Muscarinic acetylcholine receptor M2 antagonist, Muscarinic acetylcholine receptor M3 antagonist Muscarinic acetylcholine receptor M3 Muscarinic Receptor Agonists and Antagonists: Effects on Cancer 8.7 6.237205357 predicted 4.819267444
VASOPRESSIN Vasopressin receptor agonist Oxytocin receptor The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a … 7.249908608 6.795507674 predicted 5.450990369
VASOPRESSIN Vasopressin receptor agonist Peripheral myelin protein 22 Identification of molecular markers for metastasis-related genes in … 7.192464972 6.795507674 predicted 5.450990369
VASOPRESSIN Vasopressin receptor agonist Vasopressin V1a receptor Effects of Angiotensin, Vasopressin and Aldosterone on Proliferation … 8.8604 6.795507674 predicted 5.450990369
VASOPRESSIN Vasopressin receptor agonist Vasopressin V1b receptor Effects of Angiotensin, Vasopressin and Aldosterone on Proliferation … 8.80201944 6.795507674 predicted 5.450990369
VASOPRESSIN Vasopressin receptor agonist Vasopressin V2 receptor Effects of Angiotensin, Vasopressin and Aldosterone on Proliferation … 9.208746573 6.795507674 predicted 5.450990369
DAUNORUBICIN HYDROCHLORIDE DNA inhibitor, DNA topoisomerase II alpha inhibitor Isocitrate dehydrogenase [NADP] cytoplasmic Human DNA topoisomerase II-alpha: A new … – ScienceDirect.com 7.136082623 6.881199616 predicted 3.424770902
LANATOSIDE C Geminin Spotlight on Geminin | Breast Cancer Research | Full Text 6.236174637 7.08825 actual 5.444662098
LANATOSIDE C Mothers against decapentaplegic homolog 3 Mothers against decapentaplegic homolog 3 – Wikipedia 5.850011544 7.08825 actual 5.444662098
LANATOSIDE C Nuclear factor erythroid 2-related factor 2 Perspectives of the Nrf-2 signaling pathway in cancer progression and … 6.786135376 7.08825 actual 5.444662098
LANATOSIDE C Nuclear receptor ROR-gamma Nuclear Receptor ROR Gamma Market: Production, Revenue, Industry … 5.15 7.08825 actual 5.444662098
ULIMORELIN Ghrelin agonist Ghrelin receptor Ghrelin receptor agonists as novel breast cancer therapeutics – Figshare 7.57 7.1380625 predicted 6.961990852
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Androgen Receptor Targeting the Androgen Receptor in Breast Cancer – The ASCO Post 5.961823919 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor ATPase family AAA domain-containing protein 5 Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related … 6.836242476 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Bile acid receptor FXR The farnesoid X receptor is expressed in breast cancer and regulates … 6.349984048 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Cellular tumor antigen p53 The Role of the p53 Tumour Suppressor Gene in Human Breast Cancer 7.5 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor DNA topoisomerase II beta Topoisomerases II alpha and beta as therapy targets in breast cancer … 5 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Geminin Spotlight on Geminin | Breast Cancer Research | Full Text 6.755689089 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Isocitrate dehydrogenase [NADP] cytoplasmic Isocitrate dehydrogenases in physiology and cancer: biochemical and … 6.68613278 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Microtubule-associated protein tau Microtubule-associated protein tau: A marker of paclitaxel … – NCBI – NIH 5 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Mothers against decapentaplegic homolog 3 Mothers against decapentaplegic homolog 3 – Wikipedia 5.900008766 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Nuclear factor erythroid 2-related factor 2 Perspectives of the Nrf-2 signaling pathway in cancer progression and … 6.758747049 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Nuclear factor NF-kappa-B p105 subunit NF-kappa B genes have a major role in Inflammatory Breast Cancer … 7.488835312 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Peripheral myelin protein 22 Identification of molecular markers for metastasis-related genes in … 4.992188234 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Peroxisome proliferator-activated receptor delta A novel peroxisome proliferator-activated receptor delta … – NCBI 6.571489509 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Peroxisome proliferator-activated receptor gamma The role of peroxisome proliferator-activated receptor-γ in breast cancer. 6.500038134 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Prelamin-A/C The clinicopathological significance of lamin A/C, lamin B1 and lamin … 6.05 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Proto-oncogene c-JUN c-Jun Induces Mammary Epithelial Cellular Invasion and Breast … 6.664221565 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Retinoid X receptor alpha A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha … 7.62503913 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Serum albumin Serum albumin as a modulator on growth of the human breast cancer … 6.453498209 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Signal transducer and activator of transcription 3 Signal transducer and activator of transcription-3 and breast cancer … 6.15 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Sodium/potassium-transporting ATPase Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related … 8.1 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Solute carrier organic anion transporter family member 1B1 Tumor-Specific Expression of Organic Anion-Transporting – Hindawi 5.113249546 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Solute carrier organic anion transporter family member 1B3 Tumor-Specific Expression of Organic Anion-Transporting – Hindawi 5.304539675 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Solute carrier organic anion transporter family member 4C1 Tumor-Specific Expression of Organic Anion-Transporting – Hindawi 6.92 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Thyroid hormone receptor beta-1 Targeting Thyroid Hormone Receptor Beta in Triple Negative Breast … 7.149966742 7.398125 actual 4.314638489
DIGITOXIN Sodium/potassium-transporting ATPase inhibitor Vitamin D receptor Vitamin D receptor as a target for breast cancer therapy. – NCBI 6.250031916 7.398125 actual 4.314638489
SIMEPREVIR NS3/4A Protease Inhibitor Cathepsin S Cathepsin S Mediates Brain-Specific Breast Cancer Metastasis … 6.1 7.40790625 predicted 4.549179982
MORICIZINE Glucagon-like peptide 1 receptor Glucagon-like peptide-1 receptor agonists and risk of breast cancer. 5.099999035 7.481649319 predicted 3.501628141
MORICIZINE Histone acetyltransferase GCN5 Histone acetyltransferase inhibitors block neuroblastoma cell growth … 6.7000571 7.481649319 predicted 3.501628141
MORICIZINE Histone-lysine N-methyltransferase, H3 lysine-9 specific 3 Histone lysine methyltransferases as anti-cancer targets for drug … 6.049976093 7.481649319 predicted 3.501628141
MORICIZINE Hypoxia-inducible factor 1 alpha Hypoxia-inducible factor 1 and breast cancer metastasis – NCBI – NIH 5.8 7.481649319 predicted 3.501628141
MORICIZINE Peripheral myelin protein 22 Identification of molecular markers for metastasis-related genes in … 7.060480747 7.481649319 predicted 3.501628141
MORICIZINE Prelamin-A/C The clinicopathological significance of lamin A/C, lamin B1 and lamin … 9.397940009 7.481649319 predicted 3.501628141
PODOFILOX Unknown Androgen Receptor Targeting the Androgen Receptor in Breast Cancer – The ASCO Post 5.413058858 7.967625 actual 5.031382053
PODOFILOX Unknown ATPase family AAA domain-containing protein 5 ATAD5 ATPase family, AAA domain containing 5 [ (human)] – NCBI 7.036212173 7.967625 actual 5.031382053
PODOFILOX Unknown Cytochrome P450 2C19 CYP2C19*17 is associated with decreased breast cancer risk. – NCBI 5.3 7.967625 actual 5.031382053
PODOFILOX Unknown Cytochrome P450 2C9 Tamoxifen inhibits cytochrome P450 2C9 activity: A possible … 5.4 7.967625 actual 5.031382053
PODOFILOX Unknown DNA-(apurinic or apyrimidinic site) lyase Extreme Expression of DNA Repair Protein Apurinic/Apyrimidinic … 5.950007143 7.967625 actual 5.031382053
PODOFILOX Unknown Geminin Spotlight on Geminin | Breast Cancer Research | Full Text 7.816272425 7.967625 actual 5.031382053
PODOFILOX Unknown Hypoxia-inducible factor 1 alpha Hypoxia-inducible factor 1 and breast cancer metastasis – NCBI – NIH 7.8 7.967625 actual 5.031382053
PODOFILOX Unknown Isocitrate dehydrogenase [NADP] cytoplasmic Isocitrate dehydrogenases in physiology and cancer: biochemical and … 6.68613278 7.967625 actual 5.031382053
PODOFILOX Unknown Nuclear factor erythroid 2-related factor 2 Perspectives of the Nrf-2 signaling pathway in cancer progression and … 6.215896349 7.967625 actual 5.031382053
PODOFILOX Unknown Nuclear receptor subfamily 0 group B member 1 noRefFound 5.67 7.967625 actual 5.031382053
PODOFILOX Unknown Peripheral myelin protein 22 Identification of molecular markers for metastasis-related genes in … 7.771271006 7.967625 actual 5.031382053
PODOFILOX Unknown Peroxisome proliferator-activated receptor delta A novel peroxisome proliferator-activated receptor delta … – NCBI 7.092246988 7.967625 actual 5.031382053
PODOFILOX Unknown Prelamin-A/C The clinicopathological significance of lamin A/C, lamin B1 and lamin … 7.525 7.967625 actual 5.031382053
PODOFILOX Unknown Proto-oncogene c-JUN c-Jun activation is associated with proliferation and angiogenesis in … 6.84075338 7.967625 actual 5.031382053
PODOFILOX Unknown Solute carrier organic anion transporter family member 1B1 Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related … 5.247460693 7.967625 actual 5.031382053
PODOFILOX Unknown Solute carrier organic anion transporter family member 1B3 noRefFound 6.296222689 7.967625 actual 5.031382053
PODOFILOX Unknown Tubulin Tubulin protein: MCF-7 cancer cell – Cytoskeleton, Inc. 5.502602119 7.967625 actual 5.031382053
CLARITHROMYCIN Bacterial 70S ribosome inhibitor Solute carrier organic anion transporter family member 1B1 Lee 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 article 5.353893659 8.242964275 predicted 4.461185566
CLARITHROMYCIN Bacterial 70S ribosome inhibitor Solute carrier organic anion transporter family member 1B3 Uptake transporter organic anion transporting polypeptide 1B3 … – NCBI 5.38706858 8.242964275 predicted 4.461185566
AZITHROMYCIN Bacterial 70S ribosome inhibitor Geminin Spotlight on Geminin | Breast Cancer Research | Full Text 5.399129213 8.247836908 predicted 4.66093881
AZITHROMYCIN Bacterial 70S ribosome inhibitor Isocitrate dehydrogenase [NADP] cytoplasmic Isocitrate dehydrogenases in physiology and cancer: biochemical and … 5.236212739 8.247836908 predicted 4.66093881
AZITHROMYCIN Bacterial 70S ribosome inhibitor Prelamin-A/C The clinicopathological significance of lamin A/C, lamin B1 and lamin … 6.2 8.247836908 predicted 4.66093881
AZITHROMYCIN Bacterial 70S ribosome inhibitor Retinoid X receptor alpha A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha … 5.350003493 8.247836908 predicted 4.66093881
AZITHROMYCIN Bacterial 70S ribosome inhibitor TAR DNA-binding protein 43 TARDBP regulates glycolysis in hepatocellular carcinoma by … 5.350003493 8.247836908 predicted 4.66093881
AZITHROMYCIN Bacterial 70S ribosome inhibitor Transcription factor AP-1 The AP-1 transcription factor regulates breast cancer cell … – NCBI 5 8.247836908 predicted 4.66093881
METILDIGOXIN Androgen Receptor Targeting the Androgen Receptor in Breast Cancer – The ASCO Post 6.498232935 8.317873512 predicted 2.885625
CLARITHROMYCIN Bacterial 70S ribosome inhibitor Streptokinase A Amicoumacin A induces cancer cell death by targeting the … – Nature 7.22184875 8.242964275 predicted 4.461185566
AZITHROMYCIN Bacterial 70S ribosome inhibitor Streptokinase A Amicoumacin A induces cancer cell death by targeting the … – Nature 7.22184875 8.247836908 predicted 4.66093881