Types Of Cancer Cell Lines Research Articles

Systematic pan-cancer analysis showed that RAD51AP1 was associated with immune microenvironment, tumor stemness, and prognosis.

Although RAD51 associated protein 1 (RAD51AP1) is crucial in genome stability maintenance, it also promotes cancer development with an unclear mechanism. In this study, we collected intact expression data of RAD51AP1 from the public database, and verified it was significantly over-expressed in 33 cancer types and correlated with poor prognosis in 13 cancer types, including glioma, adrenocortical carcinoma, lung adenocarcinoma. We further authenticated that RAD51AP1 is up-regulated in several typical cancer cell lines and promotes cancer cell proliferation in vitro. Moreover, we also demonstrated that RAD51AP1 was significantly positively related to cancer stemness score mRNAsi in 27 cancer types and broadly correlated to tumor-infiltrating immune cells in various cancers in a diverse manner. It was also negatively associated with immunophenoscore (IPS) and Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) scores and positively correlated with mutant-allele tumor heterogeneity (MATH), tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression in multiple cancers. The tumor stemness enhancing and tumor immune microenvironment affecting functions of RAD51AP1 might compose its carcinogenesis mechanism. Further investigations beyond the bioinformatics level should confirm these findings in each specific cancer.

PLAC1 affects cell to cell communication by interacting with the desmosome complex

IntroductionX-linked PLAC1 is highly expressed in placenta during embryogenesis, and when ablated in mice, causes aberrant placental cell layer organization. It is also highly expressed in many types of cancer cell-lines. Although it has been shown that it promotes AKT phosphorylation in cancer cells, the exact mechanism by which it influences placental layer differentiation is unclear. MethodsTo investigate the mechanism of action of PLAC1 we did cell fractionation and immunoprecipitation of the protein and Mass Spectrometry analysis to identify its interaction partners. The associated proteins were directly tested for interactions by co-transfection with PLAC1 and immunoprecipitation. Mutations in the ZP-N domain of PLAC1 were introduced to assess its involvement in the interactions. ResultsWe provide evidence that Desmoglein-2 (DSG2), a component of the membrane-associated desmosomal complex, directly interacts with PLAC1. Mutations of cysteines in ZP-N domain disrupt the interaction between PLAC1 and DSG-2. DiscussionBecause desmosomes are responsible for establishing lateral cell-cell junctions, we suggest that direct interaction with the lateral junction protein complex may be implicated in the PLAC1 effects on cell-cell interactions, and thereby on the layer structure of the placenta.

A comparative study of cold atmospheric plasma treatment, chemical versus physical strategy

To date, reactive oxygen species and reactive nitrogen species have been regarded as the key factors causing the observable cellular death of cold atmospheric plasma (CAP)-treated cancer cells. The chemical basis of the conventional CAP treatment highlights apoptosis as the main CAP-triggered cell death mechanism. However, we recently demonstrated a strong anti-melanoma effect based on physically-based CAP treatment. In this study, we compared the anti-cancer effect of chemically-based versus physically-based CAP treatment on four typical cancer cell lines in vitro. Three of these cancer cell lines were more sensitive to the physical factors in CAP than the chemical factors in CAP, while the fourth cell line followed the original trend of being more sensitive to chemical factors. This study demonstrated that the physically-based CAP treatment could be an effective anti-cancer approach, which might have a deep impact on the future application of CAP in medicine.

F-box protein FBXO31 modulates apoptosis and epithelial-mesenchymal transition of cervical cancer via inactivation of the PI3K/AKT-mediated MDM2/p53 axis

AimsCervical cancer (CC) is one of the most common malignant tumours in the world and a serious threat to women's health. The dysregulation of protein degradation mediated by F-box proteins is involved in tumorigenesis, and F-box protein FBXO31 has been reported to play an important role in various human cancers. However, the role of FBXO31 in CC remains unclear. This study aimed to investigate the function and underlying regulatory mechanism of FBXO31 in CC. Main methodsIn this study, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure target gene expression; the Cell Counting Kit-8, cell death ELISA, Transwell invasion assay, wound-healing assay and western blot were applied to assess cell viability, apoptosis, invasion, migration and epithelial-mesenchymal transition (EMT), respectively. Key findingsFBXO31 was expressed at a low level in 37 pairs of CC tissues and three types of CC cell lines. Overexpression of FBXO31 inhibited cell viability, invasion, migration, EMT and induced apoptosis in SiHa cells. FBXO31 promoted p53 activity through suppression of murine double minute 2 (MDM2) expression. Overexpression of MDM2 ameliorated the inhibitory effect of FBXO31 on SiHa cells, while the MDM2/p53 axis-specific inhibitor Nutlin-3a facilitated this inhibitory effect. Further, we confirmed that FBXO31 inactivated MDM2/p53 axis dependence on the phospholipid inositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. SignificanceCollectively, our results reveal that FBXO31 down-regulates CC progression by blocking the PI3K/AKT-mediated MDM2/p53 axis, suggesting that FBXO31 may serve as a promising therapeutic target for CC treatment.

Uses of cyclohexane-1,3-dione for the synthesis of 1,2,4-triazine derivatives as anti-proliferative agents and tyrosine kinases inhibitors.

Tetrahydrobenzo[b]thiophene derivatives were well known to be biologically active compounds and many of them occupy a wide range as anticancer agent drugs. One of our main aim of this work was to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of novel 1,2,4-triazines as efficient anticancer drugs with low cytotoxicity and good bioavailability properties using cyclohexane-1,3-dione and 3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-diazonium chloride to give the 2-(2-(2,6-dioxocyclohexylidene)hydrazinyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) as the key starting material for many heterocyclization reactions. Compound 3 was reacted with phenylisothiocyanate to give the tetrahydrobenzo[e][1,2,4]triazine derivative 5 which reacted with hydrazines to give dihydrazone derivatives. In addition, it underwent multi-component reactions with aromatic aldehydes and either malononitrile or ethyl cyanoacetate in the presence of triethylamine or ammonium acetate to produce fused pyran and fused pyridine derivatives, respectively. Compounds obtained in this work were evaluated for their c-Met kinase inhibitory potency as well as in-vitro cytotoxic activity against the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). Molecular modeling studies were carried out for the most active compounds 5, 7a, 7b, 10c, 10e, 11c and 11f using Molecular Operating Environment (MOE) software. It was found that all the tested compounds displayed potent c-Met enzymatic activity with IC50 values ranging from 0.24 to 9.36nM. Ten of them (5, 7a, 7b, 10c, 10e, 10f, 11b, 11c, 11d and 11f) exhibited higher potency with IC50 values less than 1.00nM compared with foretinib (IC50=1.16nM). Also those compounds possessed moderate to strong cytotoxicity against the six tested cancer cell lines in the single-digit µM range. The synthesized compounds 5, 7a, 7b, 10c, 10e, 11c and 11f were fit on the active site of c-Met kinase, with almost the same binding pattern as foretinib and higher binding energy scores (from -16.38 to -18.21kcal/mol) compared to foretinib (-16.37kcal/mol). A series of novel 1,2,4-triazines were synthesized and displayed potent bioactivities, indicating that these compounds could be considered as a new lead for more investigation in the future.

Synthesis of Tetrahydrobenzo[b]thiophene-3-carbohydrazide Derivatives as Potential Anti-cancer Agents and Pim-1 Kinase Inhibitors.

Tetrahydrobenzo[b]thiophene derivatives are well known to be biologically active compounds and many of them occupy a wide range of anticancer agent drugs. One of the main aim of this work was to synthesize target molecules not only possessing anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of 4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbohydrazide derivatives using cyclohexan-1,4-dione and cyanoacetylhydrazine to give the 2-amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbohydrazide (3) as the key starting material for many heterocyclization reactions. Compound 3 was reacted with some aryldiazonium salts and the products were cyclised when reacted with either malononitrile or ethyl cyanoacetate. Thiazole derivatives were also obtained through the reaction of compound 3 with phenylisothiocyanate followed by heterocyclization with α-halocarbonyl derivatives. Pyrazole, triazole and pyran derivatives were also obtained. The compounds obtained in this work were evaluated for their in-vitro cytotoxic activity against c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The results of anti-proliferative evaluations and c-Met kinase, Pim-1 kinse inhibitions revealed that some compounds showed high activities. The most promising compounds 5b, 5c, 7c, 7d, 11b, 14a, 16b, 18b, 19, 21a, 23c, 23d and 23i against c-Met kinase were further investigated against the five tyrosin kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 5b, 5c, 7d, 7e, 11b, 11c, 16c, 16d, 18c, 19, 23e, 23k and 23m were selected to examine their Pim-1 kinase inhibitions activity where compounds 7d, 7e, 11b, 11c, 16d, 18c and 23e showed high activities. All of the synthesized compounds have no impaired effect toward the VERO normal cell line.

Synthesis, and anti-proliferative, Pim-1 kinase inhibitors and molecular docking of thiophenes derived from estrone

Heterocyclization of steroids were reported to give biologically active products where ring D modification occured. Estrone (1) was used as a template to develop new heterocyclic compounds. Ring D modification of 1 through its reaction with cyanoacetylhydrazine and elemental sulfur gave the thiophene derivative 3. The latter compound reacted with acetophenone derivatives 4a-c to give the hydrazide-hydrazone derivatives 5a-c, respectively. In addition, compound 3 formed thiazole derivatives through its first reaction with phenylisothiocyanate to give the thiourea derivative 9 followed by the reaction of the later with α-halocarbonyl compounds. In the present work a series of novel estrone derivatives were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase, and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). The most promising compounds 5b, 5c, 11a, 13c, 15b, 15c, 15d, 17a and 17b were further investigated against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR. Compounds 5b, 15d, 17a and 17b were selected to examine their Pim-1 kinase inhibition activity where compounds 15d and 17b showed high activities. Molecular docking of some of the most potent compounds was demonstrated.

Uses of dimedone for the synthesis of thiazole derivatives as new anti-tumor, c-Met, tyrosine kinase, and Pim-1 inhibitions

A series of heterocyclic compounds derived from dimedone were synthesized through the first reaction of dimedone with elemental sulfur and phenylisothiocyanate followed by heterocyclization of the produced thiazole derivative through its reaction with different chemical reagents. All the synthesized compounds were determined by elemental analysis, 1H NMR, 13C NMR, and MS. The newly synthesized compounds were evaluated for their in vitro cytotoxic activity against c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). All target compounds were initially tested for their anti-proliferative activity against human prostatic cancer PC-3 cell line. The most promising compounds 5a, 7a, 7b, 9c, 9d, 9i, 9k, 12a, 12d, 14b, and 15d were further investigated against tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 7a, 7b, 9c, 9d, 9k, 14b, and 15c were selected to examine their Pim-1 kinase inhibition activity where compounds 7a, 9d, 9k, and 15c showed high activities.

Uses of dimedone for the synthesis of new heterocyclic derivatives with anti-tumor, c-Met, tyrosine, and Pim-1 kinases inhibitions

The reaction of dimedone (1) with any of the diazonium salts 2a–c to give the arylhydrazone derivatives 3a–c. The Gewald’s reaction of any of compounds 3a–c using elemental sulfur and either of malononitrile or ethyl cyanoacetate gave the thiophene derivatives 5a–f, respectively. Compounds 5a, 5c, and 5e underwent a series of heterocclization reactions to give potentially anticancer agents. The newly synthesized compounds were evaluated for their in vitro cytotoxic activity against c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). All target compounds were initially tested for their anti-proliferative activity against human prostatic cancer PC-3 cell line. The most promising compounds were 5c, 6c, 6d, 8e, 8f, 12d, 14e, and 14f were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5c, 5d, 6c, 6d, 8f, 8g, 8h, 12c, 12d, 12f, and 14f were selected to examine their Pim-1 kinase inhibition activity where compounds 3c, 6c, 8g, 12c, and 14f showed high activities.

Synthesis and biological evaluation of nannocystin analogues toward understanding the binding role of the (2R,3S)-Epoxide in nannocystin A

Nannocystin A is a potent antiproliferative cyclodepsipeptide targeting eukaryotic translation elongation factor 1α. To elucidate the binding role of its (2R,3S)-epoxide, we designed and synthesized a focused library of 10 nannocystin analogues. Variable temperature NMR experiments demonstrated the importance of the (2R,3S)-epoxide in controlling the macrocyclic conformation. Biological evaluation of these compounds against three typical cancer cell lines established a clear structure-activity relationship at the epoxide region, which was rationalized by comparing the superimposed conformations of different nannocystin analogues and in silico docking analysis. Our results showed that the (2R,3S)-epoxide of nannocystin A is mainly responsible for controlling the macrocyclic conformation, rather than binding directly to the target.

The uses of cyclohexan-1,4-dione for the synthesis of thiophene derivatives as new anti-proliferative, prostate anticancer, c-Met and tyrosine kinase inhibitors

A series of heterocyclic compounds derived from the dihydrobenzo[b]thiophene derivatives were synthesized all the synthesized compounds were determined by elemental analysis, 1H NMR, 13C NMR, and MS. The newly synthesized compounds were evaluated for their in-vitro cytotoxic activity against c-Met kinase, and the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). All target compounds were initially tested for their anti-proliferative activity against human prostatic cancer PC-3 cell line. The most promising compounds were 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 7b, 7c, 11c, 11d, and 11f were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 5e, 5f, 5h, 11d, and 11f were selected to examine their Pim-1 kinase inhibition activity where compounds 5e, 5h, and 11f showed high activities.

Synthesis and biological evaluation of novel 6,11-dihydro-5H-benzo[e]pyrimido- [5,4-b][1,4]diazepine derivatives as potential c-Met inhibitors

Over expression of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein a series of novel 6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4]diazepine derivatives were designed, synthesised and evaluated for their c-Met kinase inhibition. Compounds 17e, 17f, 18a, and 18b were further examined for their anti-proliferative activities against four typical cancer cell lines (PC-3, Panc-1, HepG2, and Caki-1). The promising compound 17f was identified as a multi-target receptor tyrosine kinase inhibitor, which also displayed favourable pharmacokinetic properties in rats, had an acceptable safety profile in preclinical studies, and significant anti-tumour activity in the Caki-1 tumour xenograft model.

Synthesis and evaluation of pyrazolo[5,1-b]quinazoline-2-carboxylate, and its thiazole derivatives as potential antiproliferative agents and Pim-1 kinase inhibitors

The multi-component reactions of compounds 2a–c with any of the aromatic aldehydes 3a–c and cyclohexane-1,4-dione gave the 2-hydroxy-5,6,8,9-tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives 5a–i, respectively. In addition compounds 5a–i reacted with elemental sulfur and phenylisothiocyanate to give the 8-hydroxy-3-phenyl-4,5,7,11-tetrahydropyrazolo[5,1-b]thiazolo[5,4-f]quinazoline-2(3H)-thione derivatives 7a–i. Compounds 5a–i were reacted with cyanoacetylhydrazine to give the 2-cyano-N′-(2-hydroxy-5,6-dihydropyrazolo[5,1-b]quinazolin-7(3H,8H,9H)-ylidene)acetohydrazide derivatives 9a–i. The reaction compounds 9a–i with elemental sulfur and phenylisothiocyanate and with thioglycollic acid gave the thiazole derivatives 11a–i and 13a–i, respectively. In the present work a series of novel quinazoline and their fused derivatives were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase, prostate cancer cell lines and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The most promising compounds 5b, 5h, 5i, 7h, 9h, 9i, 11b, 11c, 11e, 13h, and 13i were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 5h, 5i, 11e, and 13i were selected to examine their Pim-1 kinase inhibition activity where compounds 5i and 11e showed high activities. All target compounds were initially tested for their anti-proliferative activity against human prostatic cancer PC-3 cell line.

Synthesis of tetrahydropyrazolo-quinazoline and tetrahydropyrazolo-pyrimidocarbazole derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors

The multi-component reactions of arylhydrazopyrazoles 2, aromatic aldehydes 3 and cylohexane-1,3-dione gave pyrazoloquinazolinones 5. In addition, compounds 5 reacted with elemental sulfur and either of malononitrile or ethyl cyanoacetate to give the thiophene derivatives 7, respectively. Compounds 5 were used to synthesis the 5,6,11,12-tetrahydro-3H-pyrazolo[1’,5’:1,2]pyrimido[5,4-a]carbazol-2-ol derivatives 9 through their reaction with phenylhydrazine. Similarly, the reaction of the pyrazole derivatives 2, with 3 and dimedone (10) gave the quinoline derivatives 11. The newly synthesized products were evaluated against c-Met kinase, PC-3 prostate cancer cell lines and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The most promising compounds were 5b, 5c, 5e–i, 7e, 7p, 7q, 7r, and 11i were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Some compounds were selected to examine their Pim-1 kinase inhibition activity where compounds 5h and 7u showed high inhibitions.

A Novel Cancer Nanotheranostics System Based on Quantum Dots Encapsulated by a Polymer-Prodrug with Controlled Release Behaviour

A nanotheranostic system is a new system that combines both diagnosis and treatment of a malignant disease, e.g. cancer, by exploitation of the unusual properties of nano-sized particles. In this project, we have developed a novel nanotheranostic system based on quantum dots (QDs) coated with drug-loaded polymer. We first synthesized a double-group functionalized amphiphilic triblock copolymer and loaded it with the anti-tumour drug paclitaxel (PTX) and lipoic acid (LA) to obtain the prodrug mPEG-block-PCL-(graft-PTX)-block-PLA-(graft-LA) (mPEG: methoxy polyethylene glycol, PLA: poly(norbornene-lactide)s). When exposed to UV light (365 nm), the disulfide bond of LA was broken into two sulfydryls, which could in turn adhere to the surface of CdSe/ZnS QDs to form a nanotheranostic system. This novel system exhibited good controlled drug release behaviour due to the ester linkage between the drug and polymer. By using typical cancer cell lines, we showed that this nanotheranostic system is promising in cancer diagnosis and treatment in vitro.

Discovery of a novel 6,7-disubstituted-4-(2-fluorophenoxy)quinolines bearing 1,2,3-triazole-4-carboxamide moiety as potent c-Met kinase inhibitors

A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro cytotoxic activities against four typical cancer cell lines (A549, H460, HT-29, and MKN-45). Most compounds showed moderate-to-excellent antiproliferative activity. Compounds 32, 36, 37, 45, 51, and 52 were further examined for their inhibitory activity against c-Met kinase. The promising compound 37, with a c-Met IC50 value of 2.27 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The analysis of their structure–activity relationships indicated that compounds with EWGs, especially chloro group, at 2-position on the phenyl ring (moiety B) have potent antitumor activity.

Abstract 2646: Building a powerful ADCs discovery and development platform with novel dolastatin/auristatin payloads

Abstract A family of novel warheads derived from dolastatins or auristatins were designed and synthesized. They showed similar or better antitumor activities against several typical cancer cell lines compared with dolastatin 10 or monomethylauristatin E or F. The conjugated ADCs with Trastuzumab have showed potent activities against Her2 breast cancer cell lines. The validated platform with novel cytotoxins can be potentially used to ADCs discovery and development. Citation Format: Shanghui Hu, Lucy X. Zhao, Xu Liu, Chao Li, Wei Hu, Zunrong Wang, Xufang Tian. Building a powerful ADCs discovery and development platform with novel dolastatin/auristatin payloads. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2646. doi:10.1158/1538-7445.AM2014-2646

Discovery andw biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors

A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five typical cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG). Most compounds showed moderate to excellent antiproliferative activity. In this study, a promising compound 34, with a c-Met IC50 value of 1.04nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The SAR analyses indicated that compounds with halogen group, especially fluoro group, at 4-position on the phenyl ring (moiety B) have potent antitumor activity, and methylation on the 5-atom linker played an important role in the c-Met enzymatic activity.

Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors

A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure–activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.

The tau-path test for monotone association in an unspecified subpopulation: Application to chemogenomic data mining

In data mining and other settings, there is sometimes a need to identify relationships between variables when the relationship may hold only over a subset of the observations available. For example, expression of a particular gene may cause resistance to an anticancer drug, but only over certain types of cancer cell-lines. It may not be known in advance which types of cancer cell-lines (e.g., estrogen-regulated, newly differentiated, central nervous system) employ such a method of resistance. This situation differs from the usual setting in which partial correlations are estimated conditional on a known selection, such as the value of another variable. For any pair of variables of interest, the goal is to test if these are associated in some unspecified subpopulation that is represented by a subsample of the data we have available. Previous approaches rely heavily on bivariate normal assumptions, which are not easily adapted to non-linear association. We have tried several parametric and non-parametric approaches, and for both inferential and computational reasons have chosen to present a procedure based on a sequential development of Kendall’s tau measure of monotone association. The sequence is achieved by reordering observations so that the sample tau coefficients { T k } for the first k = 2 , … , n of the n observations form a monotone decreasing path, ending at Kendall’s tau coefficient T n . Boundaries are constructed so that 95% of the paths remain within the boundaries under the null hypothesis of independence. A boundary crossing at any point k is evidence of a stronger than expected association amongst a subpopulation represented by the k observations involved. The method is used to screen for association between gene expression and compound activity amongst types of cancer cell-lines in the NCI-60 database. More generally, the method may be used to deconvolve a mixture of absolutely continuous bivariate distributions with the same margins but differing in strength of association. We prove that a particular method of reordering the observations is optimal against any other ordering for simultaneously identifying the highest τ association in subsets of size k ( k = 2 , … , n ) . Furthermore, assuming a subpopulation of k , we present a way of quantifying how likely any observation is to be in that subpopulation.