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  1. Article ; Online: Identification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancer.

    Dilday, Tinslee / Abt, Melissa / Ramos-Solís, Nicole / Dayal, Neetu / Larocque, Elizabeth / Oblak, Adrian L / Sintim, Herman O / Yeh, Elizabeth S

    Cell chemical biology

    2024  

    Abstract: Human epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target ... ...

    Abstract Human epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target for primary and resistant HER2+ breast cancers. In this study, a selective inhibitor of HUNK is characterized alongside a phosphorylation event in a downstream substrate of HUNK as a marker for HUNK activity in HER2+ breast cancer. Rubicon has been established as a substrate of HUNK that is phosphorylated at serine (S) 92. Findings indicate that HUNK-mediated phosphorylation of Rubicon at S92 promotes both autophagy and tumorigenesis in HER2/neu+ breast cancer. HUNK inhibition prevents Rubicon S92 phosphorylation in HER2/neu+ breast cancer models and inhibits tumorigenesis. This study characterizes a downstream phosphorylation event as a measure of HUNK activity and identifies a selective HUNK inhibitor that has meaningful efficacy toward HER2+ breast cancer.
    Language English
    Publishing date 2024-01-25
    Publishing country United States
    Document type Journal Article
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2024.01.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Nicotinamide-Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds.

    Larocque, Elizabeth / Chu, Elizabeth Fei Yin / Naganna, Nimmashetti / Sintim, Herman O

    ACS omega

    2020  Volume 5, Issue 6, Page(s) 2690–2698

    Abstract: Ponatinib is a multikinase inhibitor that is used to treat chronic myeloid leukemia patients harboring mutated ABL1(T315I) kinase. Due to the potent inhibition of FLT3, RET, and fibroblast growth factor receptors (FGFRs), it is also being evaluated ... ...

    Abstract Ponatinib is a multikinase inhibitor that is used to treat chronic myeloid leukemia patients harboring mutated ABL1(T315I) kinase. Due to the potent inhibition of FLT3, RET, and fibroblast growth factor receptors (FGFRs), it is also being evaluated against acute myeloid leukemia (AML), biliary, and lung cancers. The multikinase inhibition profile of ponatinib may also account for its toxicity, thus analogs with improved kinase selectivity or different kinase inhibition profiles could be better tolerated. The introduction of nitrogen into drug compounds can enhance efficacy and drug properties (a concept called "necessary nitrogen"). Here, we introduce additional nitrogen into the benzamide moiety of ponatinib to arrive at nicotinamide analogs. A nicotinamide analogue of ponatinib, HSN748, retains activity against FLT3, ABL1, RET, and PDGFRα/β but loses activity against c-Src and P38α. MNK1 and 2 are key kinases that phosphorylate eIF4E to regulate the protein translation complex. MNK also modulates mTORC1 signaling and contributes to rapamycin resistance. Inhibitors of MNK1 and 2 are being evaluated for anticancer therapy. Ponatinib is not a potent inhibitor of MNK1 or 2, but the nicotinamide analogs are potent inhibitors of MNKs. This illustrates a powerful demonstration of the necessary nitrogen concept to alter both the potency and selectivity of drugs.
    Language English
    Publishing date 2020-02-04
    Publishing country United States
    Document type Journal Article
    ISSN 2470-1343
    ISSN (online) 2470-1343
    DOI 10.1021/acsomega.9b03223
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Targeting RET Solvent-Front Mutants with Alkynyl Nicotinamide-Based Inhibitors.

    Khatri, Ujjwol / Dayal, Neetu / Hu, Xueqing / Larocque, Elizabeth / Naganna, Nimishetti / Shen, Tao / Liu, Xuan / Holtsberg, Frederick W / Aman, M Javad / Sintim, Herman O / Wu, Jie

    Molecular cancer therapeutics

    2023  Volume 22, Issue 6, Page(s) 717–725

    Abstract: Selpercatinib (LOXO292) and pralsetinib (BLU667) are RET protein tyrosine kinase inhibitors (TKIs) recently approved for treating RET-altered cancers. However, RET mutations that confer selpercatinib/pralsetinib resistance have been identified, ... ...

    Abstract Selpercatinib (LOXO292) and pralsetinib (BLU667) are RET protein tyrosine kinase inhibitors (TKIs) recently approved for treating RET-altered cancers. However, RET mutations that confer selpercatinib/pralsetinib resistance have been identified, necessitating development of next-generation RET TKIs. While acquired RET G810C/R/S/V mutations were reported in selpercatinib-treated patients, it was unclear whether all of these and other potential G810 mutants are resistant to selpercatinib and pralsetinib. Here, we profiled selpercatinib and pralsetinib on all six possible G810 mutants derived from single nucleotide substitution and developed novel alkynyl nicotinamide-based RET TKIs to inhibit selpercatinib/pralsetinib-resistant RET G810 mutants. Surprisingly, the G810V mutant found in a clinical study was not resistant to selpercatinib or pralsetinib. Besides G810C/R/S, G810D also conferred selpercatinib/pralsetinib resistance. Alkynyl nicotinamide compounds such as HSN608, HSL476, and HSL468 have better drug-like properties than alkynyl benzamides. Six of these compounds inhibited all six G810 solvent-front mutants and the V804M gatekeeper mutant with IC50 < 50 nmol/L in cell culture. Oral administration of HSN608 at a well-tolerated dose (30 mg/kg) gave plasma level > 30x the IC50s of inhibiting all G810 mutants in cell culture. In cell-derived xenograft tumors driven by KIF5B-RET (G810C) that contains the most frequently observed solvent-front mutant in selpercatinib-treated patients, HSN608, HSL476, and HSL468 significantly suppressed and caused regression of the selpercatinib-resistant tumors. This study clarifies the sensitivities of different RET solvent-front mutants to selpercatinib and pralsetinib and identifies novel alkylnyl nicotinamide-based RET TKIs for inhibiting selpercatinib/pralsetinib-resistant G810 mutants.
    MeSH term(s) Humans ; Administration, Oral ; Benzamides/pharmacology ; Cell Culture Techniques ; Niacinamide/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-ret
    Chemical Substances HSN608 ; Benzamides ; Niacinamide (25X51I8RD4) ; Protein Kinase Inhibitors ; RET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-ret (EC 2.7.10.1)
    Language English
    Publishing date 2023-04-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-22-0629
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5750: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Alkynylnicotinamide-Based Compounds as ABL1 Inhibitors with Potent Activities against Drug-Resistant CML Harboring ABL1(T315I) Mutant Kinase.

    Larocque, Elizabeth A / Naganna, N / Opoku-Temeng, Clement / Lambrecht, Alyssa M / Sintim, Herman O

    ChemMedChem

    2018  Volume 13, Issue 12, Page(s) 1172–1180

    Abstract: The introduction of imatinib into the clinical scene revolutionized the treatment of chronic myelogenous leukemia (CML). The overall eight-year survival rate for CML has increased from about 6 % in the 1970s to over 90 % in the imatinib era. However, ... ...

    Abstract The introduction of imatinib into the clinical scene revolutionized the treatment of chronic myelogenous leukemia (CML). The overall eight-year survival rate for CML has increased from about 6 % in the 1970s to over 90 % in the imatinib era. However, about 20 % of CML patients harbor primary or acquired resistance to tyrosine kinase inhibitors. ABL1 point mutations in the BCR-ABL1 fusion protein, such as ABL1(T315I), typically emerge after prolonged kinase inhibitor treatment. Ponatinib (AP24534) is currently the only approved CML drug that is active against the ABL1(T315I) mutation. However, ponatinib has severe cardiovascular toxicities; hence, there have been efforts to find safer CML drugs that work against ABL1 secondary mutations. We reveal that isoquinoline- or naphthyridine-based compounds, such as HSN431, HSN576, HSN459, and HSN608 potently inhibit the enzymatic activities of ABL1, ABL1(T315I), and ABL1(E255K). These compounds inhibit the proliferation of ABL1-driven CML cell lines, K652 and KCL22 as well as the drug-resistant cell line, KCL22-IR, which harbors the secondary mutated ABL1(T315I) kinase.
    MeSH term(s) Alkynes/chemical synthesis ; Alkynes/chemistry ; Alkynes/pharmacology ; Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Humans ; Imatinib Mesylate/pharmacology ; Imidazoles/pharmacology ; Isoquinolines/chemical synthesis ; Isoquinolines/chemistry ; Isoquinolines/pharmacology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Mice ; Molecular Docking Simulation ; Naphthyridines/chemical synthesis ; Naphthyridines/chemistry ; Naphthyridines/pharmacology ; Niacinamide/analogs & derivatives ; Niacinamide/chemical synthesis ; Niacinamide/chemistry ; Niacinamide/pharmacology ; Point Mutation ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-abl/antagonists & inhibitors ; Proto-Oncogene Proteins c-abl/chemistry ; Proto-Oncogene Proteins c-abl/genetics ; Pyridazines/pharmacology ; Quinazolines/chemical synthesis ; Quinazolines/chemistry ; Quinazolines/pharmacology
    Chemical Substances Alkynes ; Antineoplastic Agents ; Imidazoles ; Isoquinolines ; Naphthyridines ; Protein Kinase Inhibitors ; Pyridazines ; Quinazolines ; Niacinamide (25X51I8RD4) ; ponatinib (4340891KFS) ; Imatinib Mesylate (8A1O1M485B) ; ABL1 protein, human (EC 2.7.10.2) ; Proto-Oncogene Proteins c-abl (EC 2.7.10.2)
    Language English
    Publishing date 2018-05-22
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.201700829
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6280: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Aminoisoquinoline benzamides, FLT3 and Src-family kinase inhibitors, potently inhibit proliferation of acute myeloid leukemia cell lines.

    Larocque, Elizabeth / Naganna, N / Ma, Xiaochu / Opoku-Temeng, Clement / Carter-Cooper, Brandon / Chopra, Gaurav / Lapidus, Rena G / Sintim, Herman O

    Future medicinal chemistry

    2017  Volume 9, Issue 11, Page(s) 1213–1225

    Abstract: Aim: Mutated or overexpressed FLT3 drives about 30% of reported acute myeloid leukemia (AML). Currently, FLT3 inhibitors have shown durable clinical responses but a complete remission of AML with FLT3 inhibitors remains elusive due to mutation-driven ... ...

    Abstract Aim: Mutated or overexpressed FLT3 drives about 30% of reported acute myeloid leukemia (AML). Currently, FLT3 inhibitors have shown durable clinical responses but a complete remission of AML with FLT3 inhibitors remains elusive due to mutation-driven resistance mechanisms. The development of FLT3 inhibitors that also target other downstream oncogenic kinases may combat the resistance mechanism.
    Results: 4-substituted aminoisoquinoline benzamides potently inhibit Src-family kinases and FLT3, including secondary mutations, such as FLT3D835. Modifications of aminoisoquinoline benzamide to aminoquinoline or aminoquinazoline abrogated FLT3 and Src-family kinase binding.
    Conclusion: The lead aminoisoquinolines potently inhibited FLT3-driven AML cell lines, MV4-11 and MOLM-14. These aminoisoquinoline benzamides represent new kinase scaffolds with high potential to be translated into anticancer agents.
    MeSH term(s) Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/pharmacology ; Apoptosis ; Benzamides/chemical synthesis ; Benzamides/pharmacology ; Binding Sites ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Humans ; Isoquinolines/chemical synthesis ; Isoquinolines/pharmacology ; Leukemia, Myeloid, Acute/drug therapy ; Molecular Docking Simulation ; Mutation ; Protein Binding ; Protein Conformation ; fms-Like Tyrosine Kinase 3/antagonists & inhibitors ; src-Family Kinases/antagonists & inhibitors
    Chemical Substances Antineoplastic Agents ; Benzamides ; Isoquinolines ; FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2017
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1756-8927
    ISSN (online) 1756-8927
    DOI 10.4155/fmc-2017-0067
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in mice.

    Naganna, N / Opoku-Temeng, Clement / Choi, Eun Yong / Larocque, Elizabeth / Chang, Elizabeth T / Carter-Cooper, Brandon A / Wang, Modi / Torregrosa-Allen, Sandra E / Elzey, Bennett D / Lapidus, Rena G / Sintim, Herman O

    EBioMedicine

    2019  Volume 40, Page(s) 231–239

    Abstract: Background: Acute myeloid leukemia (AML) remains one of the most lethal, rarely cured cancers, despite decades of active development of AML therapeutics. Currently, the 5-year survival of AML patients is about 30% and for elderly patients, the rate ... ...

    Abstract Background: Acute myeloid leukemia (AML) remains one of the most lethal, rarely cured cancers, despite decades of active development of AML therapeutics. Currently, the 5-year survival of AML patients is about 30% and for elderly patients, the rate drops to <10%. About 30% of AML patients harbor an activating mutation in the tyrosine kinase domain (TKD) of Fms-Like Tyrosine kinase 3 (FLT3) or a FLT3 internal tandem duplication (FLT3-ITD). Inhibitors of FLT3, such as Rydapt that was recently approved by the FDA, have shown good initial response but patients often relapse due to secondary mutations in the FLT3 TKD, like D835Y and F691 L mutations.
    Methods: Alkynyl aminoisoquinoline and naphthyridine compounds were synthesized via Sonogashira coupling. The compounds were evaluated for their in vitro and in vivo effects on leukemia growth.
    Findings: The compounds inhibited FLT3 kinase activity at low nanomolar concentrations. The lead compound, HSN431, also inhibited Src kinase activity. The compounds potently inhibited the viability of MV4-11 and MOLM-14 AML cells with IC50 values <1 nM. Furthermore, the viability of drug-resistant AML cells harboring the D835Y and F691 L mutations were potently inhibited. In vivo efficacy studies in mice demonstrated that the compounds could drastically reduce AML proliferation in mice.
    Interpretation: Compounds that inhibit FLT3 and downstream targets like Src (for example HSN431) are good leads for development as anti-AML agents. FUND: Purdue University, Purdue Institute for Drug Discovery (PIDD), Purdue University Center for Cancer Research, Elks Foundation and NIH P30 CA023168.
    MeSH term(s) Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Humans ; Isoquinolines/chemistry ; Isoquinolines/pharmacology ; Leukemia, Myeloid, Acute ; Mice ; Molecular Structure ; Mutation ; Naphthyridines/chemistry ; Naphthyridines/pharmacology ; Protein Kinase Inhibitors/pharmacology ; fms-Like Tyrosine Kinase 3/antagonists & inhibitors ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/metabolism ; src-Family Kinases/antagonists & inhibitors ; src-Family Kinases/metabolism
    Chemical Substances Antineoplastic Agents ; Isoquinolines ; Naphthyridines ; Protein Kinase Inhibitors ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; src-Family Kinases (EC 2.7.10.2) ; isoquinoline (JGX76Y85M6)
    Language English
    Publishing date 2019-01-25
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2019.01.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7090: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  7. Article: Identification of New FLT3 Inhibitors That Potently Inhibit AML Cell Lines via an Azo Click-It/Staple-It Approach.

    Ma, Xiaochu / Zhou, Jie / Wang, Changhao / Carter-Cooper, Brandon / Yang, Fan / Larocque, Elizabeth / Fine, Jonathan / Tsuji, Genichiro / Chopra, Gaurav / Lapidus, Rena G / Sintim, Herman O

    ACS medicinal chemistry letters

    2017  Volume 8, Issue 5, Page(s) 492–497

    Abstract: Acute myeloid leukemia (AML) is an aggressive malignancy with only a handful of therapeutic options. About 30% of AML patients harbor mutated FLT3 kinase, and thus, this cancer-driver has become a hotly pursued AML target. Herein we report a new class of ...

    Abstract Acute myeloid leukemia (AML) is an aggressive malignancy with only a handful of therapeutic options. About 30% of AML patients harbor mutated FLT3 kinase, and thus, this cancer-driver has become a hotly pursued AML target. Herein we report a new class of FLT3 inhibitors, which potently inhibit the proliferation of acute myeloid leukemia (AML) cells at nanomolar concentrations.
    Language English
    Publishing date 2017-04-14
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.6b00468
    Database MEDical Literature Analysis and Retrieval System OnLINE

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