DIAGNOSTIC METHOD

Abstract

The present invention is in the field of cancer diagnosis. In particular, the present invention relates to a method for determining in a cancer patient the risk of develop a resistance to chemical substances used in cancer therapy. The invention furthermore provides a novel combination therapy for patients that have been diagnosed to develop drug resistance against chemical substances used for treating cancer.

Claims

1. Method for the determination whether a cancer or tumor cell will develop resistance to a chemical substance, wherein the method comprises the following steps: a) exposure of one or more sample(s) comprising or consisting of cancer or tumor cells obtained from a subject diagnosed with cancer to a chemical substance, wherein the subject diagnosed with cancer has not previously been administered with the chemical substance; b) determining the expression level of a gene associated with the development of cancer drug resistance in the one or more sample(s) used in a); c) determining the expression level of the same gene as in b) in the one or more sample(s) from the subject diagnosed with cancer that is (are) not exposed to the chemical substance used in a); wherein an elevated expression level determined in b) compared to the expression level determined in c) is indicative of the development of resistance to the chemical substance by a cancer or tumor cell comprised in said sample.

2. A method for determining whether a subject previously diagnosed with cancer will develop resistance to a chemical substance used for treating said cancer, wherein the method comprises the following steps: a) exposure of one or more sample(s) comprising or consisting of cancer of tumor cells obtained from the subject diagnosed with cancer to a chemical substance, wherein the subject diagnosed with cancer has not previously been administered with the chemical substance; b) determining the expression level of a gene associated with the development of cancer drug resistance in the one or more sample(s) used in a); c) determining the expression level of the same gene as in b) in the one or more sample(s) from the subject diagnosed with cancer that is (are) not exposed to the chemical substance used in a); wherein the subject diagnosed with cancer has not been administered with the chemical substance used in a) prior to obtaining the one or more sample(s) and wherein an elevated expression level determined in b) compared to the expression level determined in c) is indicative of the development of resistance to the chemical substance by the patient.

3. The method of claim 1 or claim 2, wherein the one or more samples) is obtained by biopsy.

4. The method of claim 1 or claim 2, wherein the sample is obtained from circulating tumor cells in the blood.

5. The method of any one of the preceding claims, wherein the gene associated with the development of resistance is a gene selected from the group consisting of SOX2, Nanog, OCT4, FGF4, FBX15, FOXP4, KLF9, CD24, CD271, CD36, ITLN2, TNFSF12, NOX3, CLEC7A, ACYAP1, UNC5C, UNC5D, UC16, VAV3, FOXD3, VGLL3, ALPP C3, F2R ENPP2 ETV4, NTNG1 NTRK2, ROBO1 and ROBO2.

6. The method of claim 5 wherein the gene associated with the development of resistance is SOX2.

7. The method of any one of the preceding claims, wherein cancer is non-melanoma skin cancer, esophagogastric adenocarcinoma, glioblastoma, bladder cancer, bladder urothelial carcinoma, esophagogastric cancer, melanoma, non-small cell lung cancer, endometrial cancer, cervical adenocarcinoma, esophageal squamous cell carcinoma, breast cancer, head and neck squamous cell carcinoma, germ cell tumor, small cell lung cancer, ovarian cancer, soft tissue sarcoma, hepatocellular carcinoma, colorectal adenocarcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, prostate cancer, upper tract urothelial carcinoma, diffuse glioma, colorectal cancer, ampullary carcinoma, adrenocortical carcinoma, head and neck cancer, renal clear cell carcinoma, hepatobiliary cancer, glioma, non-Hodgkin lymphoma, mesothelioma, salivary gland cancer, renal non-clear cell carcinoma, miscellaneous neuroepithelial tumor, pheochromocytoma, thymic tumor, multiple myeloma, renal cell carcinoma, bone cancer, pancreatic cancer, leukemia, peripheral nervous system tumors, thyroid cancer, B-lymphoblast leukemia, monoclonal B-cell lymphocytosis, lymphoma, hairy cell leukemia, acute myeloid leukemia, Wilms tumor in particular melanoma and non-small cell lung cancer.

8. The method of any one of the preceding claims, wherein said chemical substance is an inhibitor of a receptor tyrosine kinase (RTK), the EGFR pathway (EGFRi) or an inhibitor of the MAPK pathway (MAPKi), wherein, preferably, said MAPKi is an inhibitor of B-Raf (BRAFi), an inhibitor of MEK (MEKi), or an inhibitor of ERK (ERKi).

9. The method according to claim 8, wherein said i) said BRAFi is vemurafenib, dabrafenib, encorafenib, LGX818, PLX4720, TAK-632, MLN2480, SB590885, XL281, BMS-908662, PLX3603, RO5185426, GSK2118436 or RAF265, ii) said MEKi is AZD6244, trametinib, selumetinib, cobimetinib, binimetinib, MEK162, RO5126766, GDC-0623, PD 0325901, CI-1040, PD-035901, hypothemycin or TAK-733, iii) said ERKi is ulixertinib, corynoxeine, SCH772984, XMD8-92, FR 180204, GDC-0994, ERK5-IN-1, DEL-22379, BIX 02189, ERK inhibitor (CAS No. 1049738-54-6), ERK inhibitor III (CAS No. 331656-92-9), GDC-0994, honokiol, LY3214996, CC-90003, deltonin, VRT752271, TIC10, astragaloside IV, XMD8-92, VX-11e, mogrol, or X11e, and/or iv) said EGFRi is cetuximab, panitumumab, zalutuumab, nimotuzumab, matuzumab, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, necitumumab, osimertinib, afatinib, AP26113, EGFR inhibitor (CAS No. 879127-07-8), EGFR/ErbB-2/ErbB-4 Inhibitor (CAS No. 881001-19-0), EGFR/ErbB-2 Inhibitor (CAS No. 179248-61-4), EGFR inhibitor II (BIBX 1382,CAS No. 196612-93-8), EGFR inhibitor III (CAS No. 733009-42-2), EGFR/ErbB-2/ErbB-4 Inhibitor II (CAS No. 944341-54-2) or PKCII/EGFR Inhibitor (CAS No. 145915-60-2).

10. A chemical substance for use in treating cancer in patients determined to develop resistance to said chemical substance using the method of any one of claims 1 to 7, in combination with a second chemical substance, wherein said second chemical substance inhibits expression of a gene associated with the development of cancer drug resistance.

11. Use of one or more chemical substances for treating patients determined to developed resistance to said chemical substances using the methods of any one of claims 1-7 in combination with a further chemical substance which inhibits the expression of one or more genes associated with the development of cancer drug resistance to the first chemical substance or substances.

12. A product containing a combination of one or more chemical substances determined to induce cancer drug resistance in a cancer of tumor cell using the methods of any one of claims 1-7 and a further chemical substance which inhibits the expression of one or more genes associated with the development of cancer drug resistance to the first chemical substance.

13. The chemical substance for use of claim 10, the use of claim 11 and the product of claim 12, wherein cancer is non-melanoma skin cancer, esophagogastric adenocarcinoma, glioblastoma, bladder cancer, bladder urothelial carcinoma, esophagogastric cancer, melanoma, non-small cell lung cancer, endometrial cancer, cervical adenocarcinoma, esophageal squamous cell carcinoma, breast cancer, head and neck squamous cell carcinoma, germ cell tumor, small cell lung cancer, ovarian cancer, soft tissue sarcoma, hepatocellular carcinoma, colorectal adenocarcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, prostate cancer, upper tract urothelial carcinoma, diffuse glioma, colorectal cancer, ampullary carcinoma, adrenocortical carcinoma, head and neck cancer, renal clear cell carcinoma, hepatobiliary cancer, glioma, non-Hodgkin lymphoma, mesothelioma, salivary gland cancer, renal non-clear cell carcinoma, miscellaneous neuroepithelial tumor, pheochromocytoma, thymic tumor, multiple myeloma, renal cell carcinoma, bone cancer, pancreatic cancer, leukemia, peripheral nervous system tumors, thyroid cancer, B-lymphoblast leukemia, monoclonal B-cell lymphocytosis, lymphoma, hairy cell leukemia, acute myeloid leukemia, Wilms tumor in particular melanoma and non-small cell lung cancer.

14. The chemical substance for use of claim 10 or claim 13, the use of claim 11 or claim 13 and the product of claim 12 or claim claim 13, wherein said chemical substance is an inhibitor of a receptor tyrosine kinase (RTK), the EGFR pathway (EGFRi), an inhibitor of the MAPK pathway (MAPKi) or an agent used in immunotherapy of cancer, wherein, preferably, said MAPKi is an inhibitor of B-Raf (BRAFi), an inhibitor of MEK (MEKi), or an inhibitor of ERK (ERKi).

15. The chemical substance for use, the use and the product of claim 14, wherein said i) said BRAFi is vemurafenib, dabrafenib, encorafenib, LGX818, PLX4720, TAK-632, LN2480, SB590885, XL281, BMS-908662, PLX3603, RO5185426, GSK2118436 or RAF265, ii) said MEKi is AZD6244, trametinib, selumetinib, cobimetinib, binimetinib, MEK162, RO5126766, GDC-0623, PD 0325901, CI-1040, PD-035901, hypothemycin or TAK-733, iii) said ERKi is ulixertinib, corynoxeine, SCH772984, XMD8-92, FR 180204, GDC-0994, ERK5-IN-1, DEL-22379, BIX 02189, ERK inhibitor (CAS No. 1049738-54-6), ERK inhibitor III (CAS No, 331656-92-9), GDC-0994, honokiol, LY3214996, CC-90003, deltonin, VRT752271, TIC10, astragaloside IV, XMD8-92, VX-11e, mogrol, or VTX11e, iv) said EGFRi is cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, necitumumab, osimertinib, afatinib, AP26113, EGFR inhibitor (CAS No. 879127-07-8), EGFR/ErbB-2/ErbB-4 Inhibitor (CAS No. 881001-19-0), EGFR/ErbB-2 Inhibitor (CAS No. 179248-61-4), EGFR inhibitor II (BIBX 1382,CAS No. 196612-93-8), EGFR inhibitor III (CAS No. 733009-42-2), EGFR/ErbB-2/ErbB-4 Inhibitor II (CAS No. 944341-54-2) or PKCII/EGFR Inhibitor (CAS No. 145915-60-2); and/or v) said agent used in immunotherapy is an agent targeting CD52, PD-L1, CTLA4, CD20, or PD-1. Agents that may be used in combination with a compound of the present invention include, for example, alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, rituximab.

16. The chemical substance for use of any one of claims 10, and 13 to 15, the use of any one of claims 11 and 13 to 15 and the product any one of claims 12 and 13 to 15, wherein said second chemical substance inhibiting expression of a gene associated with the development of cancer drug resistance inhibits a gene selected from the group consisting of SOX2, Nanog, OCT4, FGF4, FBX15, FOXP4, KLF9, CD24, CD271, CD36, ITLN2, TNFSF12, NOX3, CLEC7A, ACYAP1, UNCSC, UNC5D, MUC16, VAV3, FOXD3, VGLL3, ALPP, C3, F2R, ENPP2, ETV4, NTNG1, NTRK2, ROBO1 and ROBO2.

17. The chemical substance for use, the use and the product of claim 16, wherein the gene associated with the development of resistance is SOX2.

18. The chemical substance for use of any one of claims 10 and 13 to 18, the use of any one of claims 11 and 13 to 18 and the product any one of claims 12 and 13 to 18, wherein said second chemical substance is selected from the group consisting of cetrimonium bromide, idarubicin.hcl, neratinib (hki-272), benzyl isothiocyanate, vorinostat, emetine dihydrochloride, daunorubicin hydrochloride, dactinomycin, quisinostat (jnj26481585), niclosamide, doxorubicin, pci-24781 (abexinostat), lanatoside c, panobinostat (lbh589), salinomycin, sodium, broxaldine, teniposide, pracinostat (sb939), azacitidine, homoharringtonine, acrisorcin, tolonium chloride, radotinib, amodiaquine dihydrochloride, benzethonium chloride, chidamide, cudc-101, selamectin, tetrandrine, belinostat (pxd101), etravirine (tmc125), amcinonide, oxibendazole, acetyl-l-leucine, chloroxine, napabucasin, resminostat, idoxuridine, tioguanine, cycloheximide, trifiuridine, betamethasone 17,21, dipropionate, dovitinib (tki-258) dilactic acid, colchicine, mocetinostat (mgcd0103), sunitinib, pelitinib (ekb-569), pimavanserin , efloxate, tg101348 (sar302503), clobetasol propionate, methylprednisolone sodium succinate, dichlorisone acetate, albendazole, entinostat (ms-275), flunisolide, artenimol, aminacrine, flumethasone, rocilinostat (acy-1215), bronopol, gramicidin (gramicidin a shown), abamectin (avermectin b1a shown), disulfiram, difluprednate, acetriazoic acid, isoflupredone acetate, ly2835219, perhexiline maleate, metergoline, formestane, monensin sodium, floxuridine, prednicarbate, dexamethasone sodium phosphate, leflunomide, halobetasol propionate, sirolimus, ipriflavone, nintedanib (bibf 1120), pyrvinium, pamoate, rufloxacin hydrochloride, fosbretabulin (combretastatin a4 phosphate (ca4p)), disodium, triamcinolone diacetate, otenabant (cp-945598) hcl, aprotinin, fluticasone propionate, amuvatinib (mp-470), methylbenzethonium chloride, fenbendazole, bupivacaine hydrochloride, betamethasone, flumethazone pivalate, thioguanine, tegaserod maleate, prednisolone acetate, chlorindione, hydrocortisone hemisuccinate, dexamethasone acetate, fludrocortisone acetate, ivermectin, proflavine hemisulfate, lansoprazole, cerdulatinib (prt062070, prt2070), salifungin, halcinonide, fudosteine, terfenadine, fluocinonide, hexetidine, artesunate, fluocinolone acetonide, rifampin, triamcinolone, zolpidem, ethopropazine, hydrochloride, regorafenib (bay 73-4506), terazosin hydrochloride, tanshinone iia-sulfonic sodium, nocodazole, triclosan, clopidol, sorafenib tosylate, sulfisomidine, methylene blue, crizotinib (pf-02341066), proscillaridin a, dexibuprofen, triflupromazine hydrochloride, piribedil hydrochloride, carmofur, swertiamarin, sultamicillin tosylate, ginsenoside rc, etofibrate, cetylpyridinium chloride, rabeprazole sodium, alizapride hydrochloride, methyl aminolevulinate.hcl, topiroxostat, disodium clodronate tetrahydrate, amoxapine, bedaquiline(tmc207; r207910), octenidine, ecabet sodium, apigenin, glycopyrrolate iodide, sodium montmorillonite, hydrocortisone, barbadin, CCS1477, SGC-CBP30, CPI-637, PF-CBP1, ICG,001,PRI-724, A-485, C646, 4-methylthio-2-oxobutyric acid (MTOB), HIPP derivatives, cyclic peptide CP61, NSC95397, 2-(hydroxyimino)-3-phenylpropanoic acid and 4-chloro and 3-chloro analogues thereof, MLN4924, AS1842856, JIB-04, EP-5676, N-oxalylglycine (NOG), pyridine-2,4-dicarboxylate (2,4-PDCA), pladineolide B, IDC16 CBL0137, difopein, R18.

Description

EXAMPLE 1

Method for Determining Development of Resistance

[0098] 1. Preparation and Ex Vivo Treatment of Tumor Slices [0099] Surplus tumor tissue was stored in cold serum-free RPMI 1620 Glutamax at 4 C. for up to 24 h before processing. Large biopsies were trimmed to about 1 cm maximal diameter. [0100] A 50 ml Falcon tube was cut at the 40 ml mark and the bottom part was discarded. The biopsy was placed into the lid of the shortened Falcon tube. The tube was filled up to the 45 ml mark with with liquid 4% low temperature agarose (SeaPlaque Agarose, Lonza). The agarose was left to solidify on ice. [0101] Once solidified, the agarose block was removed from the Falcon tube and trimmed to a rectangle. About 2 mm of agarose was left from the left and right of the tissue biopsy. About 5 mm of agarose was left from the top and bottom of the tissue biopsy to prevent the tissue from being pushed out of the agarose during the cutting procedure. [0102] The trimmed agarose block was glued onto the specimen holder of a vibratome (Leica VT1000 S Vibrating blade microtome) using cyanoacrylate adhesive and let dry at room temperature. Once dried, the specimen holder was snapped into the buffer tray and the buffer tray installed in the ice bath tray. The buffer tray was filled with ice cold PBS. The biopsy was cut into 400 m thick slices at a speed of around 0.30 mm/s and a vibration amplitude of about 0.70 mm. [0103] 1 nil PRMP 1620 Glutamax containing 1 Antibiotic-Antimycotic (Gibco) and 10% FCS was added to each well of a 6 well plate. One Millicell insert (Millicell Cell Culture Insert, 30 mm, hydrophilic PTFE, 0.4 m) was transferred into each well. Several slices were transferred onto one Millicell insert. Slices were kept in a humidified cell culture incubator (21% O.sub.2, 5% CO.sub.2) and left to recover for 24 h. [0104] After recovery, Millicell inserts were rinsed by transferring them into a well on a 6 well plate containing 1 ml PRMP 1620 Glutamax (1 Antibiotic-Antimycotic (Gibco), 10% FCS) and either 0.01% DMSO (for control biopsies) or 0.5 M Selumetinib (for treatment biopsies).

[0105] The inserts were then transferred into a fresh well containing 1 ml PRMP 1620 Glutamax (1 Antibiotic-Antimycotic (Gibco), 10% FCS) and either 0.01% DMSO (for control biopsies) or 0.5 M Selumetinib (for treatment biopsies). Biopsies were incubated for 16 h to 48 h in a humidified cell culture incubator.

[0106] 2. Gene Expression Analysis of Tumor Slices [0107] To analyze gene expression, tumor slices were transferred into 2.0 ml Eppendorf Safe-Lock microcentrifuge tube (round bottom) using sterile tweezers, weighed, flash frozen in liquid nitrogen and stored at 80 C. until further use. RNA was isolated according to manufacturer's instructions using a RNeasy Mini or Micro Kit (Qiagen) depending on tissue weight and was eluted in 10-30 l RNase-free water and stored at 80 C. RNA concentration and purity was determined spectrophotometrically using a NanoDrop 2000 (Thermo Scientific). RNA was reverse transcribed to cDNA according to manufacturer's instructions using a High-capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). Per 20 l reaction the following mix was prepared in a Roche LightCycler 480 Multiwell Plate: 3 l water, 1 l 5 M forward primer, 1 l 5 M reverse primer, 10 l LightCycler 480 SYBR Green I Master (2) or KAPA SYBR FAST qPCR Kit, 5 l cDNA [5 ng/l]. Samples were pipetted in duplicates. 96-well-plates were centrifuged for 1 min at 2000 rpm and run on a LightCylcer 480 device (Roche) using the standard qRT-PCR protocol with 45 cycles. Relative gene expression levels were calculated using the Ct method {Livak:2001is}, normalizing to GAPDH, TBP or HPRT.

[0108] Patients, whose tumor slices express more of a gene associated with the development of resistance as selected from the group comprising SOX, Nanog, OCT4, FGF4, FBX15, FOXP4, KLF9, CD24, CO271, CD36, ITLN2, TNFSFI2, NOX3, CLEC7A, ACYAPI, UNC5C, UNC5D, MUC16, VAV3, FOXD3, VGLL3, ALPP, C3, F2R, ENPP2, ETV4, NTNGI, NTRK2, ROBO1 and ROBO2 after the short-term ex vivo selumetinib treatment as compared to control-treated slices from the same tumor biopsy are likely to develop resistance against selumetinib-based cancer therapies.

[0109] 3. Immunohistochemical Analysis of Tumor Slices [0110] To prevent damage to the tissue slices, they were lifted out of Millicell inserts using small strips of nitrocellulose membrane. The strips with the tissue slices were then transferred to 4% paraformaldehye. After 24 h, nitrocellulose membrane-attached tumor slices were either transferred to 70% ethanol or directly embedded in paraffin and sectioned according to standard protocols. Paraffin sections were cooked for 20 minutes at 98 C. in EDTA buffer (pH 9) (Dako S2367) using a pressure cooker. Sections were blocked with Peroxidase Block (Dako S2023) for 10 minutes, incubated for 1 h with anti-SOX2 antibody (sc365823) diluted in Dilution Buffer (Dako S2022) to 2 g/ml, and incubated with the secondary antibody (Envision Mouse, Dako K4001) for 30 minutes. All steps were performed at room temperature. Nuclear counterstain was performed using haematoxylin solution modified according to Gill II (Merck 1051752500) for 2 seconds. After dehydration, slides were coverslipped using a Tissue-Tek Film Coverslipper (Sakura, 4742). [0111] Patients, whose tumor slices express more SOX2 after the short-term ex vivo selumetinib treatment as compared to control-treated slices from the same tumor biopsy are likely to develop resistance against selumetinib-based cancer therapies.

EXAMPLE 2

Chemical Compounds for use in Treating Cancer in Combination with a Resistance Inhibitor

[0112] 1. Screen and Acquisition [0113] On Day 1, A375 cells were seeded at 1400 cell per well into a 384 well plate in DMEM supplemented with 10% FCS and 2 mM L-Glutamine. Plates were kept in a humidified cell culture incubator (21% O.sub.2, 5% CO.sub.2) and left to recover for 16 h. On Day 2, cells were treated with PLX4720 and AZD6244 with a final concentration of 1 uM and 0.5 uM, respectively. At the same time, the cells were treated with a library of FDA-approved drugs (Table 1) with a final concentration of 5 uM. Plates were kept in a humidified cell culture incubator (21% O.sub.2, 5% CO.sub.2) and left to recover for 24 h. On Day 3, plates were three times washed with PBS and fixed with a final concentration of 2% PFA for 10 min at room temperature. [0114] Plates were washed three times with PBS and incubated with a final concentration of 0.2% Triton-X (in PBS) for 10 min at 4 C. Plates were washed three times with PBS and incubated with a final concentration of 0.2% Triton-X (in PBS) for 10 min at 4 C. Plates were washed three times with PBS and incubated with a final concentration of 1% Glycine (in PBS) for 10 min at 4 C. Plates were washed three times with PBS and incubated with a final concentration of 0.8 g/ml Sox-2 antibody (SantaCruz, E-4, sc-365823) (in 0.05% Tween 20/PBS) overnight. On Day 4, plates were washed three times with PBS. Plates were incubated with a final concentration of 2 g/ml secondary antibody (A-11029, goat anti-mouse alexa-488, 2 mg/ml) (diluted with CMF-PBS+0.05% Tween 20) for 1 h at room temperature. Plates were washed three times with PBS and incubated with a final concentration of 6.7 ug/ml propidium iodide and 0.2 mg/ml Rnase A fro 1 h at room temperature. After 1 h plates were read with an acumen cellestia (TTP Labtech). For this, fluorophores were excitied at 488 nm and signals were measured in FL3 (nuclear stainging) and FL2 (secondary antibody). The screen was run in duplicate within one month.

[0115] 2. Preprocessing [0116] Systematic variation from plate to plate is removed by standard normalization procedures (Malo, Nat Biotech, 2006). Following common practice, assay quality is evaluated on the basis of the Z factor. Within-plate row-wise or column-wise stripe patterns as well as edge effects can arise during plate preparation. These patterns are eliminated using the median polish method of Tuckey (Tukey, Reading Massachusetts: Addison-Wesley, 1977) or by subtracting a smooth polynomial using the loess function (Boutros, Genome Biology, 2006).

[0117] 3. Differential Activity Analysis

[0118] Differential activity was analyzed following the workflow sketched in Prummer et al (Prummer, J Biomol Screen, 2012). Briefly, for each single-dose measurement of a compound, a Z-test is performed against the Null hypothesis that its activity is indistinguishable from the negative controls. For this to be valid, the distribution of activities of the negative controls are checked to be normal. The mean and variance of the distribution is estimated robustly for each plate and, appropriate, smoothly averaged over a range of consecutive plates.

[0119] The semi-automated workflow is implemented in the R environment for statistical computing (Huber, Nat Methods, 2015).

TABLE-US-00001 TABLE 1 Drug. name CAS. raw norm cor. loess z pval padj DRONEDARONE 141625-93-6 0.87213341 4.00362873 3.82314631 52.0129975 0 1.42E13 HYDROCHLORIDE THIRAM 137-26-8 0.88424461 3.60299395 3.26613572 44.4350007 0 1.42E13 PENFLURIDOL 26864-56-2 0.91785544 2.4911578 2.24830134 30.5876057 0 1.42E13 PYRITHIONE ZINC 13463-41-7 0.89796146 3.23499818 3.17051487 26.1297191 0 1.42E13 THIMEROSAL 54-64-8 0.86629934 6.07392047 6.42250877 25.2453176 0 9.09E13 MITOXANTRONE 70476-82-3, 0.93739611 1.84475834 1.83801051 25.0056964 0 1.42E13 HYDROCHLORIDE 65271-80-9 [base] LDK378 1032900-25-6 0.88567874 3.41143875 3.06496564 23.9157992 0 1.42E13 PHENYLMERCURIC ACETATE 62-38-4 0.90015274 3.16718725 2.78289492 23.8811952 0 1.42E13 THIRAM 137-26-8 0.87061094 5.84893751 5.61534231 22.3535397 0 9.09E13 CETRIMONIUM BROMIDE 57-09-0, 6899-10- 0.88411767 4.7646491 5.01373006 19.5078759 0 9.09E13 1 [cetrimonium] OUABAIN OCTAHYDRATE 11018-89-6 0.93870974 1.76872708 1.68251849 18.6531299 0 1.42E13 Idarubicin-HCl 57852-57-0 0.94244724 1.67654727 1.70928639 18.2751446 0 1.42E13 AZD9291 1421373-65-0 0.92509565 2.16959587 2.0825523 16.2500689 0 1.42E13 Neratinib (HKI-272) 698387-09-6 0.90436083 4.1564606 4.18160135 16.1057509 0 9.09E13 PYRITHIONE ZINC 13463-41-7 0.8268055 8.51129482 8.61807959 15.671586 0 9.09E13 BENZYL ISOTHIOCYANATE 622-78-6 0.95384043 1.25995646 1.30518091 14.4698018 0 1.42E13 CHLOROTHALONIL 1897-45-6 0.90525187 4.07310589 3.90774183 14.0269464 0 9.09E13 YM155 (Sepantronium 781661-94-7 0.93418118 1.88335309 1.79013617 13.968358 0 1.42E13 Bromide) VORINOSTAT 149647-78-9 0.96341695 0.98399687 0.98678747 13.4250091 0 1.42E13 DIGOXIN 20830-75-5 0.94333408 1.66813301 1.62310122 13.3767482 0 1.42E13 SANGUINARIUM CHLORIDE 5578-73-4 0.94498408 1.61115323 1.49971785 12.3598872 0 1.42E13 DIGITOXIN 71-63-6 0.94679382 1.54865694 1.487977 12.2631253 0 1.42E13 YM155 (Sepantronium 781661-94-7 0.93261472 2.64602537 3.10768206 11.9694703 0 9.09E13 Bromide) EMETINE DIHYDROCHLORIDE 316-42-7, 483-18- 0.94850704 1.48949379 1.4290969 11.7778664 0 1.42E13 1 [emetine] CHLOROTHALONIL 1897-45-6 0.9594557 1.11245645 1.09494703 11.7068243 0 1.42E13 DAUNORUBICIN 20830-81-3 0.95153076 1.38507484 1.3865946 11.4275848 0 1.42E13 HYDROCHLORIDE SANGUINARIUM CHLORIDE 5578-73-4 0.87553252 5.70391993 6.07702228 11.0507888 0 9.09E13 DACTINOMYCIN 50-76-0 0.93346583 1.99004004 1.82634262 10.8038781 0 1.42E13 Quisinostat (JNJ-26481585) 875320-31-3 0.94796667 1.44903679 1.355698 10.578455 0 1.42E13 NICLOSAMIDE 50-65-7 0.97004324 0.76480106 0.72241042 9.82822222 0 1.42E13 Romidepsin (FK228, 128517-07-7 0.95059614 1.399559 1.3825506 9.78040257 0 1.42E13 Depsipeptide) Bardoxolone Methyl 218600-53-4 0.95125237 1.34551965 1.24995848 9.75337394 0 1.42E13 DOXORUBICIN 23214-92-8 0.94429955 1.61589439 1.61997959 9.58312088 0 1.42E13 MITOXANTRONE 70476-82-3, 0.94442833 1.98261811 2.3433515 9.32840738 0 9.09E13 HYDROCHLORIDE 65271-80-9 [base] PCI-24781 (Abexinostat) 783355-60-2 0.95293628 1.29246755 1.16573113 9.09615145 0 1.42E13 LANATOSIDE C 17575-22-3 0.96302575 1.04045418 1.05905089 9.08816239 0 1.42E13 Panobinostat (LBH589) 404950-80-7 0.95177866 1.32893883 1.16285765 9.07372984 0 1.42E13 SALINOMYCIN, SODIUM 55721-31-8; 0.96713651 0.81287521 0.80196008 8.8908774 0 1.42E13 53003-10-4 (acid) GENTIAN VIOLET 548-62-9 0.96008627 1.08962521 1.07693072 8.87549767 0 1.42E13 BROXALDINE 3684-48-6 0.96707764 0.81485474 0.79925633 8.86090246 0 1.42E13 TENIPOSIDE 29767-20-2 0.96668415 0.87591891 0.64457876 8.76934098 0 1.42E13 Pracinostat (SB939) 929016-96-6 0.95551467 1.21123447 1.11037175 8.66418453 0 1.42E13 AZACITIDINE 320-67-2 0.9650662 0.97143413 0.99449279 8.53416216 0 1.42E13 Homoharringtonine 26833-87-4 0.95762504 1.16115231 1.18095408 8.35427385 0 1.42E13 ACRISORCIN 7527-91-5 0.9751482 0.59593073 0.58386821 7.94338825 2.00E15 1.42E13 Quisinostat (JNJ-26481585) 875320-31-3 0.95298541 1.55702088 2.04298279 7.86870125 3.55E15 9.09E13 Idarubicin-HCl 57852-57-0 0.95670469 1.47952809 2.18837332 7.85522602 4.00E15 9.30E13 TOLONIUM CHLORIDE 92-31-9 0.97100232 0.68288694 0.70815092 7.85086832 4.22E15 2.92E13 Radotinib 926037-48-1 0.9713066 0.71941795 0.71863124 7.68337595 1.55E14 1.05E12 AMODIAQUINE 6398-98-7, 69-44-3 0.96113307 1.05347566 0.93077195 7.6709338 1.71E14 1.12E12 DIHYDROCHLORIDE [anhydrous], 86-42-0 [amodiaquine] BENZETHONIUM CHLORIDE 121-54-0 0.96351605 0.97118357 0.92876275 7.65437498 1.93E14 1.24E12 Chidamide 743420-02-2 0.96178815 1.0199474 1.06680668 7.54677538 4.46E14 2.79E12 CUDC-101 1012054-59-9 0.96149009 1.02297681 0.9584341 7.47862134 7.51E14 4.57E12 SELAMECTIN 165108-07-6 0.9768345 0.54014824 0.53298006 7.25106711 4.13E13 2.46E11 Tetrandrine 518-34-3 0.96185234 1.01777042 1.01782421 7.20026488 6.01E13 3.50E11 Ispinesib (SB-715992) 336113-53-2 0.93866419 2.32262473 1.85171565 7.13202155 9.89E13 2.11E10 Belirtostat (PXD101) 414864-00-9 0.96057989 1.05165301 0.89216711 6.96154282 3.37E12 1.91E10 Etravirine (TMC125) 269055-15-4 0.97313113 0.65890663 0.64597988 6.90661074 4.96E12 2.76E10 Ispinesib (SB-715992) 336113-53-2 0.96076213 1.04591147 0.87247738 6.80790465 9.90E12 5.39E10 OXYQUINOLINE HEMISULFATE 134-31-6 0.96646147 0.86946854 0.81755667 6.73787289 1.61E11 8.57E10 AMCINONIDE 51022-69-6 0.97609298 0.56467769 0.49099385 6.67985466 2.39E11 1.25E09 PHENYLMERCURIC ACETATE 62-38-4 0.94198189 2.09237768 1.67992944 6.60339343 4.02E11 7.91E09 Panobinostat (LBH589) 404950-80-7 0.9545552 1.47310102 1.70785251 6.57792188 4.77E11 8.72E09 OXIBENDAZOLE 20559-55-1 0.97630095 0.55779809 0.47811706 6.50466898 7.79E11 3.99E09 Belinostat (PXD101) 414864-00-9 0.94883289 1.77901194 1.67176503 6.43892825 1.20E10 2.05E08 ACETYL-L-LEUCINE 99-15-0 0.97369871 0.5922208 0.57820032 6.41017957 1.45E10 7.30E09 CHLOROXINE 773-76-2 0.97575104 0.57598873 0.47095325 6.40720704 1.48E10 7.30E09 Napabucasin 83280-65-3 0.96580916 0.88690312 0.82040308 6.40157103 1.54E10 7.43E09 BENZYL ISOTHIOCYANATE 622-78-6 0.95465515 1.41276801 1.61684724 6.29097595 3.15E10 5.05E08 Mocetinostat (MGCD0103) 726169-73-9 0.95941063 1.2135326 1.6273413 6.26782693 3.66E10 5.51E08 Resminostat 864814-88-0 0.96558788 0.89387469 0.79996504 6.24209393 4.32E10 2.05E08 IDOXURIDINE 54-42-2 0.97259781 0.71667087 0.71503283 6.13599832 8.46E10 3.94E08 TIOGUANINE 154-42-7 0.97544262 0.53358164 0.54846877 6.0805627 1.20E09 5.38E08 THIMEROSAL 54-64-8 0.9726295 0.7155989 0.70122562 6.01751282 1.77E09 7.69E08 CYCLOHEXIMIDE 66-81-9 0.97381236 0.67558781 0.6971238 5.98231342 2.20E09 9.39E08 TRIFLURIDINE 70-00-8 0.97960546 0.44848579 0.43872651 5.96876994 2.39E09 1.00E07 BETAMETHASONE 17,21- 5593-20-4 0.98005692 0.43355154 0.43562319 5.92654998 3.09E09 1.28E07 DIPROPIONATE Dovitinib (TKI-258) Dilactic 852433-84-2 0.96743384 0.83571697 0.75656854 5.90347283 3.56E09 1.45E07 Acid COLCHICINE 64-86-8 0.96925119 0.77313059 0.71106849 5.86025318 4.62E09 1.85E07 CUDC-101 1012054-59-9 0.95976785 1.19443618 1.51965288 5.85305689 4.83E09 6.86E07 Mocetinostat (MGCD0103) 726169-73-9 0.96670941 0.85854042 0.7471306 5.82982895 5.55E09 2.19E07 Sunitinib 557795-19-4 0.97749959 0.51402562 0.53851743 5.75765651 8.53E09 3.26E07 Pelitinib (EKB-569) 257933-82-7 0.96767793 0.82802704 0.73756467 5.75518637 8.65E09 3.26E07 Pimavanserin 706782-28-7 0.968867 0.79056507 0.73755355 5.7550996 8.66E09 3.26E07 EFLOXATE 119-41-5 0.95499681 1.39653254 1.46838846 5.71333908 1.11E08 1.49E06 TG101348 (SAR302503) 936091-26-8 0.96075706 1.14155362 1.47071537 5.66457042 1.47E08 1.89E06 DOXORUBICIN 23214-92-8 0.94397498 1.93369629 2.35830981 5.55413388 2.79E08 3.40E06 Dovitinib (TKI-258) Dilactic 852433-84-2 0.95253573 1.58106043 1.43565146 5.52951914 3.21E08 3.74E06 Acid PYRVINIUM PAMOATE 3546-41-6 0.94851143 1.74886846 1.39733131 5.49256902 3.96E08 4.41E06 CLOBETASOL PROPIONATE 25122-46-7, 0.9793959 0.45541808 0.40212637 5.47083379 4.48E08 1.62E06 25122-41-2 [clobetasol] PCI-24781 (Abexinostat) 783355-60-2 0.96167538 1.09246058 1.419458 5.46714883 4.57E08 4.88E06 METHYLPREDNISOLONE 03.03.2375 0.98056851 0.41662847 0.40075058 5.45211643 4.98E08 1.77E06 SODIUM SUCCINATE DICHLORISONE ACETATE 79-61-8 0.97714156 0.47645455 0.49113263 5.44490937 5.18E08 1.82E06 ALBENDAZOLE 54965-21-8 0.98109493 0.39921444 0.39774402 5.4112129 6.26E08 2.15E06 Entinostat (MS-275) 209783-80-2 0.96721246 0.8426916 0.69333717 5.41008104 6.30E08 2.15E06 AMINACRINE 90-45-9, 134-50-9 0.96000845 1.14402795 1.37355309 5.39910263 6.70E08 6.86E06 [aminacrine hydrochloride] FLUNISOLIDE 77326-96-6, 0.97366038 0.68072854 0.62791371 5.38839239 7.11E08 2.36E06 3385-03-3 OUABAIN OCTAHYDRATE 11018-89-6 0.95238129 1.52081969 1.38475854 5.38794417 7.13E08 7.02E06 ARTENIMOL 81496 81-3 0.97796256 0.44884856 0.48292025 5.35386342 8.61E08 2.83E06 Ponatinib (AP24534) 943319-70-8 0.97009615 0.75184008 0.68405408 5.33764549 9.42E08 3.05E06 AMINACRINE 90-45-9, 134-50-9 0.97370562 0.67919838 0.61358023 5.26539082 1.40E07 4.42E06 [aminacrine hydrochloride] FLUMETHASONE 2135-17-3 0.97358117 0.68340787 0.60410056 5.18404174 2.17E07 6.78E06 AZD9291 1421373-65-0 0.95730438 1.32613148 1.34471365 5.17926536 2.23E07 2.11E05 Rocihnostat (ACY-1215) 1316214-52-4 0.97054266 0.73777259 0.65765591 5.13166167 2.87E07 8.86E06 BRONOPOL 52-51-7 0.97791383 0.450487 0.45067331 4.99635985 5.84E07 1.78E05 GRAMICIDIN (gramicidin A 1405-97-6 0.97053154 0.72891573 0.59921976 4.93845468 7.87E07 2.32E05 shown) ABAMECTIN (avermectin B1a 71751-41-2 0.97789413 0.5009403 0.46062791 4.92488663 8.44E07 2.46E05 shown) ACRISORCIN 7527-91-5 0.96747792 0.77535429 1.22380691 4.87172727 1.11E06 9.77E05 DISULFIRAM 97-77-8 0.97304762 0.6420274 0.59093753 4.8701969 1.11E06 3.21E05 Difluprednate 23674-86-4 0.98005569 0.4292515 0.45288421 4.84209348 1.28E06 3.65E05 ACETRIAZOIC ACID 85-36-9, 129-63-5 0.98168618 0.37965601 0.35366324 4.81150439 1.50E06 4.21E05 [acetrizoate sodium] ISOFLUPREDONE ACETATE 338-98-7 0.97904025 0.46718275 0.35254412 4.79627899 1.62E06 4.45E05 LY2835219 1231930-82-7 0.96296373 1.02358655 1.2344393 4.75453542 1.99E06 0.00016973 PERHEXILINE MALEATE 6724 53-4, 6621- 0.97862607 0.48088372 0.3464258 4.7130407 2.44E06 6.65E05 47-2 [perhexiline] METERGOUNE 17692-51-2 0.97934661 0.40230977 0.42089336 4.66620643 3.07E06 8.27E05 PACLITAXEL 33069-62-4 0.98257921 0.35011491 0.34103977 4.63976513 3.49E06 9.30E05 FORMESTANE 566-48-3 0.9799552 0.38184606 0.41788935 4.63290263 3.61E06 9.52E05 MONENSIN SODIUM 22373-78-0 0.97614292 0.59675448 0.53594708 4.59918801 4.24E06 0.0001108 Pracinostat (SB939) 929016-96-6 0.9670443 0.80544144 1.18174429 4.55157667 5.32E06 0.00042596 FLOXURIDINE 50-91-9 0.97952104 0.45127834 0.33437653 4.54911331 5.39E06 0.00013931 PREDNICARBATE 73771-04-7 0.978218 0.4402593 0.39916716 4.42534034 9.63E06 0.00024167 DEXAMETHASONE SODIUM 2392-39-4, 312- 0.97479316 0.58174824 0.52990085 4.36716464 1.26E05 0.00031284 PHOSPHATE 93-6 [dexamethasone 21-(dihydrogen phosphate)] LEFLUNOMIDE 75706-12-6 0.98158264 0.38308121 0.31943653 4.34585809 1.39E05 0.00034149 Halobetasol Propionate 66852-54-8 0.98094293 0.39982608 0.40548008 4.33526364 1.46E05 0.00035495 SIROLIMUS 53123-88-9 0.98084386 0.40751985 0.31710492 4.31413716 1.60E05 0.00038335 IPRIFLAVONE 35212-22-7 0.98071348 0.35634856 0.38850276 4.30711018 1.65E05 0.00039206 Nintedanib (BIBF 1120) 656247-17-5 0.97437333 0.61708628 0.54849154 4.27985661 1.87E05 0.00043922 PYRVINIUM PAMOATE 3546-41-6 0.9688179 0.84452979 0.49804436 4.27392872 1.92E05 0.00044697 RUFLOXACIN HYDROCHLORIDE 106017-08-7, 0.97961558 0.44384801 0.399135 4.2674241 1.98E05 0.00045606 101363-10-4 Fosbretabulin (Combretastatin 168555-66-6 0.98140874 0.38437733 0.39809792 4.25633595 2.08E05 0.0004726 A4 Phosphate (CA4P)) Disodium TRIAMCINOLONE DIACETATE 67-78-7 0.979412 0.45059983 0.39636101 4.23776541 2.26E05 0.00050696 ISOFLUPREDONE ACETATE 338-98-7 0.96252984 1.0345188 1.06197867 4.22752184 2.36E05 0.0018213 LANATOSIDE C 17575-22-3 0.97234744 0.49489242 1.0741534 4.22223536 2.42E05 0.0018213 BROXALDINE 3684-48-6 0.96238556 1.0454252 1.06866967 4.15807692 3.21E05 0.00234743 Otenabant (CP-945598) HCl 686347-12-6 0.96647863 0.83568218 1.06864551 4.11596824 3.86E05 0.0026812 DAUNORUBICIN 20830-81-3 0.9308753 2.51538168 2.26279979 4.11479857 3.88E05 0.0026812 HYDROCHLORIDE Aprotinin 9087-70-1 0.96622985 0.99939391 1.14018378 4.09272092 4.26E05 0.00282021 Romidepsin (FK228, 128517-07-7 0.96814302 0.86910378 1.80622573 4.09093323 4.30E05 0.00282021 Depsipeptide) FLUTICASONE PROPIONATE 80474-14-2 0.97044386 0.71299307 0.68747124 4.06679196 4.77E05 0.00106106 CHLOROXINE 773-76-2 0.96835735 0.7292924 1.01834333 4.05381842 5.04E05 0.00322485 Amuvatinib (MP-470) 850879-09-3 0.97481609 0.60313686 0.51909338 4.05046399 5.11E05 0.0011258 METHYLBENZETHONIUM 1320-44-1, 0.98263238 0.34835613 0.29761114 4.04892884 5.15E05 0.0011258 CHLORIDE 25155-18-4 [anhydrous] FENBENDAZOLE 43210-67-9 0.98084656 0.43765002 0.47094603 4.04138654 5.31E05 0.00115278 BETAMETHASONE 378-44-9 0.97187427 0.51978516 1.01640799 3.99525223 6.46E05 0.00403515 BUPIVACAINE 14252-80-3 0.98350106 0.31962038 0.2933597 3.99108906 6.58E05 0.0014149 HYDROCHLORIDE DACTINOMYCIN 50-76-0 0.93875623 2.20141609 1.68790698 3.97524588 7.03E05 0.00428535 BETAMETHASONE 378-44-9 0.98099496 0.43263023 0.46233628 3.96750266 7.26E05 0.00153855 FLUMETHAZONE PIVALATE 2002-29-1, 0.97664178 0.51790904 0.4808963 3.96329484 7.39E05 0.00153855 2135-17-3 [flumethasone] THIOGUANINE 154-42-7, 0.96733045 0.75882881 0.99887156 3.9263208 8.63E05 0.00513519 5580-03-0 [hemihydrate] TEGASEROD MALEATE 189188-57-6 0.98485704 0.27476498 0.28641845 3.89665499 9.75E05 0.00199742 PREDNISOLONE ACETATE 52-21-1 0.9771695 0.49968527 0.46966514 3.87073354 0.00010851 0.00220461 CHLORINDIONE 1146-99-2 0.98249161 0.29655912 0.34626428 3.83883607 0.00012362 0.00249185 HYDROCORTISONE 83784-20-7, 0.9769567 0.50703385 0.46222171 3.80938871 0.00013931 0.00278622 HEMISUCCINATE 2203-97-6 [anhydrous] DEXAMETHASONE ACETATE 55812-90-3, 0.97690425 0.50884539 0.46148467 3.8033144 0.00014277 0.00281153 1177-87-3 [anhydrous] FLUDROCORTISONE ACETATE 514-36-3, 0.97697735 0.50632098 0.45776169 3.77263151 0.00016153 0.0031328 127-31-1 [fludrocortisone] IVERMECTIN 70288-86-7 0.97257709 0.63932157 0.63580123 3.76113383 0.00016914 0.00325572 PROFLAVINE HEMISULFATE 553-30-0, 0.98279968 0.28619997 0.3381165 3.74850618 0.00017789 0.00339851 1811-28-5 LANSOPRAZOLE 103577-45-3 0.98194159 0.37120734 0.27321749 3.71705911 0.00020156 0.00382209 Cerdulatinib (PRT062070, 1369761-01-2 0.97412848 0.6248001 0.4671962 3.64551246 0.00026686 0.00495044 PRT2070) HALCINONIDE 3093-35-4 0.98534639 0.25857767 0.2631958 3.58071637 0.00034265 0.00622123 TERFENADINE 50679-08-8 0.97666195 0.54585633 0.26014742 3.53924389 0.00040127 0.00716911 FLUOCINONIDE 356-12-7 0.9796993 0.41232308 0.42928475 3.53793951 0.00040326 0.00716911 HEXETIDINE 141-94-6 0.98342817 0.26506696 0.31545283 3.49724691 0.00047009 0.00824261 ARTESUNATE 182824-33-5 0.98353492 0.31386196 0.32464253 3.47097433 0.00051857 0.00896992 FLUOCINOLONE ACETONIDE 67-73-2 0.97907225 0.43397706 0.4201774 3.46288151 0.00053442 0.00912083 BENZOXIQUINE 86-75-9 0.97314583 0.61967992 0.58457551 3.45810394 0.00054399 0.00922264 RIFAMPIN 13292-46-1 0.97922438 0.49252149 0.40252899 3.45427103 0.00055178 0.00929318 TRIAMCINOLONE 124-94-7 0.98213259 0.39414892 0.400624 3.43792354 0.00058619 0.0098082 ZOLPIDEM 82626-48-0 0.97982598 0.44119093 0.2522452 3.43173598 0.00059973 0.00996956 NOCODAZOLE 31430-18-9 0.97658546 0.50089146 0.53110307 3.14178334 0.00167922 0.02356102 TRICLOSAN 3380-34-5 0.97534408 0.54376266 0.53095524 3.14090884 0.00168424 0.02356102 METHYLENE BLUE 7220-79-3 0.97507511 0.55305178 0.51931963 3.07207749 0.00212575 0.02894632 PROSCILLARIDIN A 466-06-8 0.9786549 0.42942253 0.50832339 3.0070283 0.00263815 0.03410944