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Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com Cell Cycle/DNA Damage Cell Cycle includes many processes necessary for successful self-replication, and consists of DNA synthesis (S) and mitosis (M) phases separated by gap phases in the order G1–S–G2–M. S phase and M phase are usually separated by gap phases called G1 and G2, when cell-cycle progression can be regulated by various intracellular and extracellular signals. In order to move from one phase of its life cycle to the next, a cell must pass through numerous checkpoints. At each checkpoint, specialized proteins determine whether the necessary conditions exist. Progression through G1 phase is controlled by pRB proteins, and phosphorylation of pRB proteins by CDKs releases E2F factors, promoting the transition to S phase. The G2/M transition that commits cells to division is a default consequence of initiating the cell cycle at the G1/S transition, many proteins, such Wee1, PLK1 and cdc25, is involved the regulation of this process. The best-understood checkpoints are those activated by DNA damage and problems with DNA replication. DNA damage response (DDR) is a series of regulatory events including DNA damage, cell-cycle arrest, regulation of DNA replication, and repair or bypass of DNA damage to ensure the maintenance of genomic stability and cell viability. Genome instability arises if cells initiate mitosis when chromosomes are only partially replicated or are damaged by a double-strand DNA break (DSB). To prevent cells with damaged DNA from entering mitosis, ATR inhibits cyclin B/Cdk1 activation by stimulating the Cdk1 inhibitory kinase Wee1 and inhibiting Cdc25C via Chk1, besides, ATM and ATR also initiate DNA repair by phosphorylating several other substrates. In cancer cells, the cell cycle regulators as well as other elements of the DDR pathway have been found to protect tumor cells from different stresses and to promote tumor progression. Thus, cell cycle proteins that directly regulate cell cycle progression (such as CDKs), as well as checkpoint kinases, Aurora kinases and PLKs, are promising targets in cancer therapy. References: [1] Rhind N, et al. Cold Spring Harb Perspect Biol. 2012 Oct; 4(10): a005942. [2] Duronio RJ, et al. Cold Spring Harb Perspect Biol. 2013 Mar; 5(3): a008904. [3] Liu W, et al. Mol Cancer. 2017 Mar 14;16(1):60. www.MedChemExpress.com 1 2 Tel: 609-228-6898 Fax: 609-228-5909 Email: [email protected] Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com Target List in Cell Cycle/DNA Damage • Antifolate 3 • Nucleoside Antimetabolite/Analog 104 • APC 7 • p97 111 • ATM/ATR 9 • PAK 113 • Aurora Kinase 12 • PARP 116 • Casein Kinase 17 • PERK 122 • CDK 20 • Polo-like Kinase (PLK) 124 • Checkpoint Kinase (Chk) 34 • PPAR 128 • CRISPR/Cas9 37 • RAD51 137 • Deubiquitinase 39 • ROCK 139 • DNA Alkylator/Crosslinker 43 • Sirtuin 144 • DNA-PK 48 • SRPK 149 • DNA/RNA Synthesis 52 • Telomerase 151 • Eukaryotic Initiation Factor (eIF) 60 • TOPK 153 • G-quadruplex 62 • Topoisomerase 155 • Haspin Kinase 64 • Wee1 163 • HDAC 66 • HSP 77 • IRE1 83 • Kinesin 86 • LIM Kinase (LIMK) 89 • Microtubule/Tubulin 91 • Mps1 101 www.MedChemExpress.com 3 Antifolate Antifolates are compounds that antagonise the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as Proguanil, Pyrimethamine and Trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR). Many are primarily DHFR inhibitors, but Raltitrexed is an inhibitor of thymidylate synthase, and Pemetrexed inhibits both and a third enzyme. Antifolates act specifically during DNA and RNA synthesis, and thus are cytotoxic during the S-phase of the cell cycle. Thus, they have a greater toxic effect on rapidly dividing cells. 4 Tel: 609-228-6898 Fax: 609-228-5909 Email: [email protected] Antifolate Inhibitors & Modulators Calcium N5-methyltetrahydrofolate Cycloguanil D6 (NSC173328) Cat. No.: HY-17557 (Chlorguanide triazine D6) Cat. No.: HY-12784S Bioactivity: Calcium N5-methyltetrahydrofolate(NSC173328) is the calcium Bioactivity: Cycloguanil D6 is the deuterium labeled Cycloguanil, which is salt of levomefolic acid, which has been proposed for a dihydrofolate reductase inhibitor. treatment of cardiovascular disease and advanced cancers such as breast and colorectal cancers. Purity: >98% Purity: 98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 5 mg, 10 mg, 50 mg, 100 mg Size: 1 mg, 5 mg, 10 mg Cycloguanil D6 Nitrate Diaveridine (Chlorguanide triazine D6 Nitrate) Cat. No.: HY-12784S1 (EGIS-5645) Cat. No.: HY-B1902 Bioactivity: Cycloguanil D6 Nitrate is the deuterium labeled Cycloguanil, Bioactivity: Diaveridine (EGIS-5645) is a dihydrofolate reductase ( DHFR) which is a dihydrofolate reductase inhibitor. inhibitor with a Ki of 11.5 nM for the wild type DHFR and also an antibacterial agent. Purity: >98% Purity: 98.48% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg Size: 10mM x 1mL in DMSO, 250 mg, 1 g, 5 g EC0489 Folinic acid Cat. No.: HY-114306 (leucovorin) Cat. No.: HY-17556 Bioactivity: EC0489, a conjugate of folic acid and desacetyl vinblastine Bioactivity: Folinic acid is an adjuvant used in cancer chemotherapy hydrazide, is a high-affinity ligand for the folate receptor involving the drug methotrexate. Target: Antifolate Folinic (FR). Refractory or metastatic Tumor [1]. Small molecule-drug acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives conjugate (SMDC) [2]. (e.g., tetrahydrofolate), and, thus, has vitamin activity that… Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: Launched Size: 500 mg, 250 mg Size: 100 mg Folinic acid Calcium Folinic acid calcium salt pentahydrate (Leucovorin Calcium; Calcium Folinate) Cat. No.: HY-13664 (Leucovorin calcium salt pentahydrate) Cat. No.: HY-B0080 Bioactivity: Leucovorin Calcium is a reduced folic acid. IC50 Value: 30 μM Bioactivity: Folinic Acid is a reduced folic acid, which is used in for zcSHMT and70 μM for zmSHMT [2] Target: Antifolate in combination with other chemotherapy drugs. Target: Folate vitro: Increasing concentrations of leucovorin (N5-CHO-THF) analog Approved: 2008 Folinic acid (calcium salt pentahydrate) inhibit both zcSHMT and hcSHMT activities substantially, yet is the calcium salt form of folinic acid, which is one of the to a lesser extent than zmSHMT. The IC50 of leucovorin is… forms of folate found naturally in foods. Folate deficiency is… Purity: 99.73% Purity: 99.73% Clinical Data: Launched Clinical Data: Launched Size: 100 mg, 500 mg Size: 100 mg, 200 mg, 500 mg Levoleucovorin Calcium Levomefolate calcium (Calcium levofolinate; CL307782) Cat. No.: HY-13667 Cat. No.: HY-17383 Bioactivity: Levoleucovorin calcium is the calcium salt of Levoleucovorin, Bioactivity: Levomefolate is an artificial form of folate. IC50 Value: which is the enantiomerically active form of folinic acid. Target: Antifolate The calcium salt of IC50 value: Target: Levoleucovorin is used to treat or prevent L-5-methyltetrahydrofolic acid which belongs to the group of toxic effects of methotrexate in people who have received folate vitamins (Vitamin B9, Folacin). It is a coenzymated methotrexate to treat bone cancer. Levoleucovorin is also used… form of folic acid and a more bioavailable alternative in… Purity: 95.24% Purity: 95.17% Clinical Data: Launched Clinical Data: Launched Size: 10mM x 1mL in Water, Size: 10 mg, 50 mg 100 mg, 500 mg, 1 g, 2 g www.MedChemExpress.com 5 LY 254155 LY309887 Cat. No.: HY-14523 Cat. No.: HY-10818 Bioactivity: LY 254155, an antifolate, inhibits hGARFT and binds to Bioactivity: LY309887 is a potent inhibitor of glycinamide ribonucleotide formyltransferase ( GARFT), with a K of 6.5 nM, and has mFBP with Kis of 2.1±0.2 and 1.7±0.1 nM, respectively. i antitumor activity. Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 250 mg, 500 mg Size: 250 mg, 500 mg Methotrexate Pemetrexed (Amethopterin; CL14377; WR19039) Cat. No.: HY-14519 (LY231514) Cat. No.: HY-10820 Bioactivity: Methotrexate is a folate antagonist, with median IC50 of 78 nM Bioactivity: Pemetrexed is a novel antifolate, the Ki values of the in in vitro assay. pentaglutamate of LY231514 are 1.3, 7.2, and 65 nM for inhibits thymidylate synthase ( TS), dihydrofolate reductase ( DHFR), and glycinamide ribonucleotide formyltransferase ( GARFT), respectively. Purity: 99.75% Purity: 99.30% Clinical Data: Launched Clinical Data: Launched Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 100 mg, 500 mg 50 mg, 100 mg Pemetrexed disodium Pemetrexed disodium hemipenta hydrate (LY231514 disodium) Cat. No.: HY-10820A (LY231514 (disodium hemipenta hydrate)) Cat. No.: HY-13781 Bioactivity: Pemetrexed disodium is a novel antifolate that inhibits the Bioactivity: Pemetrexed disodium hemipenta hydrate is a novel antifolate, folatedependent enzymes thymidylate synthase, dihydrofolate the Ki values of the pentaglutamate of LY231514 are 1.3, 7.2, reductase, and glycinamide ribonucleotide and 65 nM for inhibits thymidylate synthase ( TS), formyltransferase with
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  • Aberrant Gene Expression: Diagnostic Markers and Therapeutic Targets for Pancreatic Cancer

    Aberrant Gene Expression: Diagnostic Markers and Therapeutic Targets for Pancreatic Cancer

    ABERRANT GENE EXPRESSION: DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS FOR PANCREATIC CANCER Jeran Kent Stratford A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmacology. Chapel Hill 2014 Approved by: Jen Jen Yeh Channing J. Der Gary L. Johnson Adrienne D. Cox Timothy C. Elston © 2014 Jeran Kent Stratford ALL RIGHTS RESERVED ii ABSTRACT Jeran Kent Stratford: Aberrant gene expression: diagnostic markers and therapeutic targets for pancreatic cancer (Under the direction of Jen Jen Yeh and Channing J. Der) Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer and the fourth leading cause of cancer-related death in the United States. The overall median survival for patients diagnosed with PDAC is five to eight months. The poor outcome is due, in part, to a lack of disease-specific symptoms that can be used for early detection, and as such, most patients present with locally advanced or metastatic disease at the time of diagnosis. Therefore, the need for diagnostic tools is both great and urgent. Furthermore, current chemotherapies have low response rates and high toxicity, limiting their use, and there are currently no effective targeted therapies for PDAC. Therefore, a greater understanding of the underlying biology of pancreatic cancer is needed to identify tumor-specific vulnerabilities that can be therapeutically exploited. Pancreatic cancer development is driven by genomic changes that alter gene expression. Aberrant gene expression produces changes in protein expression, which in turn may confer growth advantages to the tumor; often the tumor then develops a dependency on continued aberrant gene and protein expression.