Anticancer Screening Compound Libraries

Cancer is a generic term for a large group of over 200 malignancies, that arise from the transformation of normal cells into malignant tumor cells. Disruption of the normal regulation of cell-cycle progression and division, and deregulated apoptosis lie at the heart of the events leading to cancer. It is responsible for about 1 in 6 deaths and is the second leading cause of death globally [1].

Therefore, the search for novel chemotherapeutic treatments for cancer is one of the most acute problems of modern pharmacology [2-4]. Recent oncology-related drug discovery research mainly focuses on targeting the key proteins for cancer survival, apoptosis regulation, immunotherapy, cancer stem cells, and tumor microenvironment.

Our team has carefully designed Anticancer Screening Libraries based on the proprietary HTS Compound Collection as a useful tool for high throughput screening (HTS) in anticancer drug discovery research. The Screening Sets comprise in total over 13,600 novel drug-like screening compounds with potential anti-tumor activity, targeting various cancer types, such as prostate and breast cancers, leukemia, lymphoma, carcinoma:

• Anticancer Focused Library by 2D Similarity Search (9,100 compounds)
• Anticancer Targeted Library by Docking (4,500 compounds)

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

Figure 1. T-lymphocytes attacking cancer cell [5].

Anticancer Focused Library by 2D Similarity Search

This Screening Compound Library of the total of 9,100 drug-like molecules was prepared by similarity search methods against publicly available databases (ChEMBL and BindingDB) of molecules with reported antitumor activity. It consists in two parts, focusing on cancer cell lines and cancer-related protein targets, respectively.

First, the Life Chemicals HTS Compound Collection was screened in silico against 12,000 reference anticancer agents with assigned activity values lower than 10 mM by similarity search and with an 80 % similarity cut-off (Tanimoto) and PAINS / reactive group filtration. The resulting selection of 1,500 structurally diversecompounds to be specially applied in cell-based phenotypic screening projects, possess potential inhibitory activity against the following cancer cell lines^*:

Subsequently, the HTS Compound Collection was filtered for analogues of molecules with known activity against different cancer-related targets, using the 75 % similarity cut-off (Tanimoto) on MDL public keys fingerprints. As a result, over 7,700 potential anti-cancer compounds were added for the following cancer-related targets^*:

All PAINS, toxic, and reactive compounds are excluded from this Screening Library, Ro5 compliance is indicated for each compound. The selection is being updated continuously with newly-synthesized molecules.

^*The results could be traced back to the specific cell lines or single cancer targets (indicated in the column “Target type” within the corresponding SD file).

Anticancer Targeted Library by Docking

The Docking Set contains around 4,500 structurally-diverse screening molecules picked out by molecular docking against the following cancer-focused drug targets:

• Multidrug resistance-associated protein 1 (MRP1)
• Tumor necrosis factor (TNF)

Multidrug resistance-associated protein 1 (MRP1)

Multidrug resistance is one of the main therapeutic problems that reduces the effectiveness of chemotherapy. MRP1 is a membrane-bound ABC transporter involved in cross-resistance to many structurally and functionally diverse classes of anticancer drugs [6]. Multidrug resistance-associated protein 1 mediates the export of organic anions and drugs from the cytoplasm [7], participates in ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs, and other xenobiotics [8]. It can also confer resistance to antitumor drugs by reducing drug accumulation in cells [9], and mediating ATP- and GSH-dependent drug export [9]. This protein also catalyzes the export of sphingosine-1-phosphate from mast cells independently of their degranulation and participates in the inflammatory response by providing the export of leukotriene C4 from leukotriene C4-synthesizing cells [11]. Therefore, MRP1 inhibition is important for cancer therapy, and it can also be used to inhibit inflammation.

Key features:

• Method: SP (standard precision) ligand-receptor docking
• X-Ray data used: 2CBZ
• Constraints: H-bond (Gly681, Ser685, Gln713) [12]
• Filters used: metabolism
• Number of compounds selected: 2113

Figure 2. Spatial structure binding site of the complex of MRP1 with lead docking molecule F1792-0080 (docking score = -9.564)

Tumor necrosis factor (TNF)

Tumor necrosis factor (TNF) is secreted by macrophages and can induce tumor death in some cell lines [13]. This protein is a powerful pyrogen and causes fever directly or through stimulation of interleukin-1 secretion. Under certain conditions, it can stimulate cell proliferation and induce cell differentiation, besides, it can impair the regulatory function of T cells in patients with rheumatoid arthritis by dephosphorylating FOXP3 [14]. A key mediator of cell death in the antitumor effect of BCG-stimulated neutrophils induces insulin resistance in adipocytes by inhibiting insulin-induced tyrosine phosphorylation of IRS1 and insulin-induced glucose uptake [15, 16] , it also induces degradation of GKAP42 protein in adipocytes, which is partially responsible for insulin resistance. This mediator plays a certain role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6. The intracellular domain form of TNF (ICD) induces IL12 production in dendritic cells [17]. TNF exerts a direct and positive effect on regulatory T cells due to its binding to the TNF receptor type 2 (TNFR2) [18]. Therefore, Tumor necrosis factor can be an important target for inhibition in a wide range of cancers and insulin resistance.

Key features:

• Method: SP (standard precision) ligand-receptor docking
• X-Ray data used: 4TSV
• Constraints: no
• Filters used: metabolism
• Number of compounds selected: 2469

Figure 3. Spatial structure binding site of the complex of TNF with lead docking molecule F5008-0111 (docking score = -6.924)

References

1. https://www.who.int/news-room/fact-sheets/detail/cancer
2. Ackova DG, Smilkov K, Bosnakovski D.Contemporary Formulations for Drug Delivery of Anticancer Bioactive Compounds // Recent Pat Anticancer Drug Discov. 2019;14(1):19-31.
3. Geromichalos GD, Alifieris CE, Geromichalou EG, Trafalis DT. Overview on the current status of virtual high-throughput screening and combinatorial chemistry approaches in multi-target anticancer drug discovery; Part I // J BUON. 2016 Jul-Aug;21(4):764-779; Part II //J BUON. 2016;21(6):1337-1358.
4. Hameed R, Khan A, Khan S, Perveen S. Computational Approaches Towards Kinases as Attractive Targets for Anticancer Drug Discovery and Development // Anticancer Agents Med Chem. 2019;19(5):592-598.
5. https://www.genengnews.com/wp-content/uploads/2020/02/Getty_177043830_CancerCell_Lymphocytes.jpg
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8. Robbiani DF, Finch RA, Jäger D, Muller WA, Sartorelli AC, Randolph GJ. The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell. 2000;103(5):757-768. doi:10.1016/s0092-8674(00)00179-3
9. Sampson A, Peterson BG, Tan KW, Iram SH. Doxorubicin as a fluorescent reporter identifies novel MRP1 (ABCC1) inhibitors missed by calcein-based high content screening of anticancer agents. Biomed Pharmacother. 2019;118:109289. doi:10.1016/j.biopha.2019.109289
10. Stride BD, Grant CE, Loe DW, Hipfner DR, Cole SP, Deeley RG. Pharmacological characterization of the murine and human orthologs of multidrug-resistance protein in transfected human embryonic kidney cells. Mol Pharmacol. 1997;52(3):344-353. doi:10.1124/mol.52.3.344
11. Mitra P, Oskeritzian CA, Payne SG, Beaven MA, Milstien S, Spiegel S. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc Natl Acad Sci U S A. 2006;103(44):16394-16399. doi:10.1073/pnas.0603734103
12. Dhasmana D, Singh A, Shukla R, Tripathi T, Garg N. Targeting Nucleotide Binding Domain of Multidrug Resistance-associated Protein-1 (MRP1) for the Reversal of Multi Drug Resistance in Cancer. Sci Rep. 2018;8(1):11973. Published 2018 Aug 10. doi:10.1038/s41598-018-30420-x
13. Pagnini C, Cominelli F. Tumor Necrosis Factor's Pathway in Crohn's Disease: Potential for Intervention. Int J Mol Sci. 2021;22(19):10273. Published 2021 Sep 24. doi:10.3390/ijms221910273
14. Nie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med. 2013;19(3):322-328. doi:10.1038/nm.3085
15. Jinesh G G, Chunduru S, Kamat AM. Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-α but not through TRAIL and FasL. J Leukoc Biol. 2012;92(1):233-244. doi:10.1189/jlb.1211623
16. Buabeid MA, Arafa EA, Hassan W, Murtaza G. In Silico Prediction of the Mode of Action of Viola odorata in Diabetes. Biomed Res Int. 2020;2020:2768403. Published 2020 Oct 31. doi:10.1155/2020/2768403
17. Nakahara H, Song J, Sugimoto M, et al. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum. 2003;48(6):1521-1529. doi:10.1002/art.11143
18. Salomon BL, Leclerc M, Tosello J, Ronin E, Piaggio E, Cohen JL. Tumor Necrosis Factor α and Regulatory T Cells in Oncoimmunology. Front Immunol. 2018;9:444. Published 2018 Mar 12. doi:10.3389/fimmu.2018.00444