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  1. AU="Ensinger, Carol L"
  2. AU="Li, Yibo"
  3. AU="DiCicco-Bloom, Emanuel"
  4. AU="Rossi, Ugo"
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  6. AU="Jia, Jianping"
  7. AU="Kuhlman, Kate R"
  8. AU="Brufsky, A"
  9. AU="SU Xian-feng"
  10. AU="Toledo, Maximiliano A"
  11. AU="Yushun Wan"
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  13. AU="Kannan, Shankar"
  14. AU="Andreyev, H Jervoise N"
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  1. Article ; Online: Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.

    Smith, Bryan D / Kaufman, Michael D / Lu, Wei-Ping / Gupta, Anu / Leary, Cynthia B / Wise, Scott C / Rutkoski, Thomas J / Ahn, Yu Mi / Al-Ani, Gada / Bulfer, Stacie L / Caldwell, Timothy M / Chun, Lawrence / Ensinger, Carol L / Hood, Molly M / McKinley, Arin / Patt, William C / Ruiz-Soto, Rodrigo / Su, Ying / Telikepalli, Hanumaiah /
    Town, Ajia / Turner, Benjamin A / Vogeti, Lakshminarayana / Vogeti, Subha / Yates, Karen / Janku, Filip / Abdul Razak, Albiruni Ryan / Rosen, Oliver / Heinrich, Michael C / Flynn, Daniel L

    Cancer cell

    2019  Volume 35, Issue 5, Page(s) 738–751.e9

    Abstract: Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT ... ...

    Abstract Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; CHO Cells ; Cell Line ; Cell Line, Tumor ; Cricetulus ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Gastrointestinal Neoplasms/drug therapy ; Gastrointestinal Neoplasms/genetics ; HCT116 Cells ; Human Umbilical Vein Endothelial Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; Mutation/drug effects ; Mutation/genetics ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-kit/genetics ; Receptor, Platelet-Derived Growth Factor alpha/genetics
    Chemical Substances Antineoplastic Agents ; Protein Kinase Inhibitors ; KIT protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1) ; Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1)
    Language English
    Publishing date 2019-05-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2019.04.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.

    Smith, Bryan D / Kaufman, Michael D / Leary, Cynthia B / Turner, Benjamin A / Wise, Scott C / Ahn, Yu Mi / Booth, R John / Caldwell, Timothy M / Ensinger, Carol L / Hood, Molly M / Lu, Wei-Ping / Patt, Tristan W / Patt, William C / Rutkoski, Thomas J / Samarakoon, Thiwanka / Telikepalli, Hanumaiah / Vogeti, Lakshminarayana / Vogeti, Subha / Yates, Karen M /
    Chun, Lawrence / Stewart, Lance J / Clare, Michael / Flynn, Daniel L

    Molecular cancer therapeutics

    2015  Volume 14, Issue 9, Page(s) 2023–2034

    Abstract: Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also ... ...

    Abstract Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.
    MeSH term(s) Aminopyridines/chemistry ; Aminopyridines/pharmacology ; Anilides/chemistry ; Anilides/pharmacology ; Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Bevacizumab/chemistry ; Bevacizumab/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Design ; Drug Resistance, Neoplasm ; Drug Therapy, Combination ; Female ; Hepatocyte Growth Factor/metabolism ; Humans ; Inhibitory Concentration 50 ; Melanoma, Experimental ; Mice ; Models, Molecular ; Molecular Conformation ; Monocytes/drug effects ; Monocytes/metabolism ; Neovascularization, Pathologic ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/chemistry ; Proto-Oncogene Proteins c-met/metabolism ; Receptor, TIE-2/antagonists & inhibitors ; Receptor, TIE-2/metabolism ; Recombinant Proteins ; Stromal Cells/drug effects ; Stromal Cells/metabolism ; Tumor Microenvironment ; Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances Aminopyridines ; Anilides ; Antineoplastic Agents ; DCC-2701 ; Protein Kinase Inhibitors ; Recombinant Proteins ; Bevacizumab (2S9ZZM9Q9V) ; Hepatocyte Growth Factor (67256-21-7) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Receptor, TIE-2 (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2015-08-18
    Publishing country United States
    Document type Journal Article ; 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-14-1105
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Novel bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines as highly potent and selective adenosine A2A receptor antagonists.

    Peng, Hairuo / Kumaravel, Gnanasambandam / Yao, Gang / Sha, Li / Wang, Joy / Van Vlijmen, Herman / Bohnert, Tonika / Huang, Carol / Vu, Chi B / Ensinger, Carol L / Chang, Hexi / Engber, Thomas M / Whalley, Eric T / Petter, Russell C

    Journal of medicinal chemistry

    2004  Volume 47, Issue 25, Page(s) 6218–6229

    Abstract: A series of bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines was synthesized. Some of these analogues show high affinity and excellent selectivity for adenosine A(2a) receptor versus the adenosine A(1) receptor. Structure- ... ...

    Abstract A series of bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines was synthesized. Some of these analogues show high affinity and excellent selectivity for adenosine A(2a) receptor versus the adenosine A(1) receptor. Structure-activity-relationship (SAR) studies based on octahydropyrrolo[1,2-a]pyrazine and octahydropyrido[1,2-a]pyrazine with various capping groups are reported. Among these analogues, the most potent and selective A(2a) antagonist 26 h has a K(i) value of 0.2 nM and is 16 500-fold selective with respect to the A(1) receptor. Among a number of compounds tested, compounds 21a and 21c exhibited significantly improved metabolic stability. Compounds 21a, 21c, and 18a showed good oral efficacy in rodent catalepsy models of Parkinson's disease.
    MeSH term(s) Adenosine A2 Receptor Antagonists ; Administration, Oral ; Animals ; Catalepsy/drug therapy ; Disease Models, Animal ; Drug Stability ; In Vitro Techniques ; Male ; Mice ; Microsomes, Liver/metabolism ; Molecular Structure ; Parkinson Disease/drug therapy ; Piperazines/chemical synthesis ; Piperazines/chemistry ; Piperazines/pharmacology ; Pyrimidines/chemical synthesis ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; Structure-Activity Relationship ; Triazines/chemical synthesis ; Triazines/chemistry ; Triazines/pharmacology ; Triazoles/chemical synthesis ; Triazoles/chemistry ; Triazoles/pharmacology
    Chemical Substances Adenosine A2 Receptor Antagonists ; Piperazines ; Pyrimidines ; Triazines ; Triazoles
    Language English
    Publishing date 2004-12-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm0494321
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Show issues Location:
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    Zs.MB 1: Show issues

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  4. Article ; Online: Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region.

    Ahn, Yu Mi / Clare, Michael / Ensinger, Carol L / Hood, Molly M / Lord, John W / Lu, Wei-Ping / Miller, David F / Patt, William C / Smith, Bryan D / Vogeti, Lakshminarayana / Kaufman, Michael D / Petillo, Peter A / Wise, Scott C / Abendroth, Jan / Chun, Lawrence / Clark, Robin / Feese, Michael / Kim, Hidong / Stewart, Lance /
    Flynn, Daniel L

    Bioorganic & medicinal chemistry letters

    2010  Volume 20, Issue 19, Page(s) 5793–5798

    Abstract: Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of ... ...

    Abstract Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.
    MeSH term(s) Adenosine Triphosphate/chemistry ; Binding Sites ; Computer Simulation ; Crystallography, X-Ray ; HeLa Cells ; Humans ; Kinetics ; Mitogen-Activated Protein Kinase 14/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 14/metabolism ; Phenylurea Compounds/chemical synthesis ; Phenylurea Compounds/chemistry ; Phenylurea Compounds/pharmacology ; Phosphorylation ; Protein Binding ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Pyrazoles/chemical synthesis ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Structure-Activity Relationship
    Chemical Substances DP 802 ; Phenylurea Compounds ; Protein Kinase Inhibitors ; Pyrazoles ; Adenosine Triphosphate (8L70Q75FXE) ; Mitogen-Activated Protein Kinase 14 (EC 2.7.11.24)
    Language English
    Publishing date 2010-10-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2010.07.134
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    Zs.A 3203: Show issues Location:
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  5. Article ; Online: Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.

    Chan, Wayne W / Wise, Scott C / Kaufman, Michael D / Ahn, Yu Mi / Ensinger, Carol L / Haack, Torsten / Hood, Molly M / Jones, Jennifer / Lord, John W / Lu, Wei Ping / Miller, David / Patt, William C / Smith, Bryan D / Petillo, Peter A / Rutkoski, Thomas J / Telikepalli, Hanumaiah / Vogeti, Lakshminarayana / Yao, Tony / Chun, Lawrence /
    Clark, Robin / Evangelista, Peter / Gavrilescu, L Cristina / Lazarides, Katherine / Zaleskas, Virginia M / Stewart, Lance J / Van Etten, Richard A / Flynn, Daniel L

    Cancer cell

    2011  Volume 19, Issue 4, Page(s) 556–568

    Abstract: Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we ...

    Abstract Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.
    MeSH term(s) Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Design ; Fusion Proteins, bcr-abl/antagonists & inhibitors ; Fusion Proteins, bcr-abl/chemistry ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Male ; Mice ; Mice, Inbred BALB C ; Mutation ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Protein Conformation ; Protein Kinase Inhibitors/pharmacology ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/chemistry
    Chemical Substances Protein Kinase Inhibitors ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Fusion Proteins, bcr-abl (EC 2.7.10.2)
    Language English
    Publishing date 2011-04-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccr.2011.03.003
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  6. Article: Syntheses and biological evaluation of vinblastine congeners.

    Kuehne, Martin E / Bornmann, William G / Markó, Istvan / Qin, Yong / LeBoulluec, Karen L / Frasier, Deborah A / Xu, Feng / Mulamba, Tshilundu / Ensinger, Carol L / Borman, Linda S / Huot, Anne E / Exon, Christopher / Bizzarro, Fred T / Cheung, Julia B / Bane, Susan L

    Organic & biomolecular chemistry

    2003  Volume 1, Issue 12, Page(s) 2120–2136

    Abstract: Sixty-two congeners of vinblastine (VLB), primarily with modifications of the piperidine ring in the carbomethoxycleavamine moiety of the binary alkaloid, were synthesized and evaluated for cytotoxicity against murine L1210 leukemia and RCC-2 rat colon ... ...

    Abstract Sixty-two congeners of vinblastine (VLB), primarily with modifications of the piperidine ring in the carbomethoxycleavamine moiety of the binary alkaloid, were synthesized and evaluated for cytotoxicity against murine L1210 leukemia and RCC-2 rat colon cancer cells, and for their ability to inhibit polymerization of microtubular protein at < 10(-6) M, and for induction of spiralization of microtubular protein, and for microtubular disassembly at 10(-4) M concentrations. An ID50 range of >10(7) M concentrations was found for L1210 inhibition by these compounds, with the most active 1000x as potent as vinblastine.
    MeSH term(s) Adenocarcinoma/drug therapy ; Animals ; Antineoplastic Agents, Phytogenic/chemical synthesis ; Antineoplastic Agents, Phytogenic/pharmacology ; Cell Line, Tumor ; Colonic Neoplasms/drug therapy ; Drug Screening Assays, Antitumor ; Inhibitory Concentration 50 ; Leukemia L1210/drug therapy ; Mice ; Microtubules/chemistry ; Microtubules/drug effects ; Rats ; Structure-Activity Relationship ; Vinblastine/analogs & derivatives ; Vinblastine/chemical synthesis ; Vinblastine/pharmacology
    Chemical Substances Antineoplastic Agents, Phytogenic ; Vinblastine (5V9KLZ54CY)
    Language English
    Publishing date 2003-08-14
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2097583-1
    ISSN 1477-0539 ; 1477-0520
    ISSN (online) 1477-0539
    ISSN 1477-0520
    DOI 10.1039/b209990j
    Database MEDical Literature Analysis and Retrieval System OnLINE

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