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  1. AU="Wang, Keshi"
  2. AU="Choi, Chi Young"
  3. AU="Mizen, Sara J"
  4. AU="Couttas, Timothy A"
  5. AU="Mendlovic, Joseph"
  6. AU="Amrhein, Carolin"
  7. AU="Türk, İlteriş"
  8. AU="Bell, T J"
  9. AU="Rapisarda, Annamaria"
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  17. AU="Jansen, Erica C"
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  21. AU="Dass, Bhagwan"
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  1. Article ; Online: A Cyclic Phosphoramidate Prodrug of 2'-Deoxy-2'-Fluoro-2'-

    Karuna, Ratna / Yokokawa, Fumiaki / Wang, Keshi / Zhang, Jin / Xu, Haoying / Wang, Gang / Ding, Mei / Chan, Wai Ling / Abdul Ghafar, Nahdiyah / Leonardi, Andrea / Seh, Cheah Chen / Seah, Peck Gee / Liu, Wei / Srinivasa, Rao P S / Lim, Siew Pheng / Lakshminarayana, Suresh B / Growcott, Ellie / Babu, Sreehari / Fenaux, Martijn /
    Zhong, Weidong / Gu, Feng / Shi, Pei-Yong / Blasco, Francesca / Chen, Yen-Liang

    Antimicrobial agents and chemotherapy

    2020  Volume 64, Issue 12

    Abstract: Monophosphate prodrug analogs of 2'-deoxy-2'-fluoro-2'- ...

    Abstract Monophosphate prodrug analogs of 2'-deoxy-2'-fluoro-2'-
    MeSH term(s) Amides ; Animals ; Antiviral Agents/pharmacology ; Dengue/drug therapy ; Dogs ; Female ; Guanosine/analogs & derivatives ; Hepacivirus ; Leukocytes, Mononuclear ; Male ; Phosphoric Acids ; Prodrugs/pharmacology ; Prodrugs/therapeutic use
    Chemical Substances 8-methylguanosine ; Amides ; Antiviral Agents ; Phosphoric Acids ; Prodrugs ; Guanosine (12133JR80S) ; phosphoramidic acid (9Q189608GB)
    Keywords covid19
    Language English
    Publishing date 2020-11-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/AAC.00654-20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 809: Show issues Location:
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  2. Article ; Online: Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma.

    Courtney, Kevin D / Infante, Jeffrey R / Lam, Elaine T / Figlin, Robert A / Rini, Brian I / Brugarolas, James / Zojwalla, Naseem J / Lowe, Ann M / Wang, Keshi / Wallace, Eli M / Josey, John A / Choueiri, Toni K

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology

    2017  Volume 36, Issue 9, Page(s) 867–874

    Abstract: Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. ... ...

    Abstract Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors ; Carcinoma, Renal Cell/blood ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/pathology ; Dose-Response Relationship, Drug ; Female ; Humans ; Indans/administration & dosage ; Indans/adverse effects ; Indans/blood ; Kidney Neoplasms/blood ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Sulfones/administration & dosage ; Sulfones/adverse effects ; Sulfones/blood
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Indans ; PT2385 ; Sulfones ; endothelial PAS domain-containing protein 1 (1B37H0967P)
    Language English
    Publishing date 2017-12-19
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 604914-x
    ISSN 1527-7755 ; 0732-183X
    ISSN (online) 1527-7755
    ISSN 0732-183X
    DOI 10.1200/JCO.2017.74.2627
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1847: Show issues Location:
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    Zs.MO 650: Show issues

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  3. Article ; Online: Correlation of Solution and Gas Phase Complexation Assessed by Electrospray Ionization Mass Spectrometry: Application to One-, Two-, and Three-Ring Macrocycles.

    Wang, Keshi / Gokel, George W.

    The Journal of organic chemistry

    1996  Volume 61, Issue 14, Page(s) 4693–4697

    Abstract: Electrospray ionization mass spectrometry (ESI-MS) was used to probe multiple cation complexation by C(12)H(25) ... (CH(2))(12) ... (CH(2))(12) ... C(12)H(25), 2, and ... CH(2)C(6)H(4)CH(2) ... , 3. Complexation of two cations (2Na(+), 2 K(+), or Na(+ ...

    Abstract Electrospray ionization mass spectrometry (ESI-MS) was used to probe multiple cation complexation by C(12)H(25)<N18N>(CH(2))(12)<N18N>(CH(2))(12)<N18N>C(12)H(25), 2, and <18N>CH(2)C(6)H(4)CH(2)<N18>, 3. Complexation of two cations (2Na(+), 2 K(+), or Na(+) and K(+)) by 3 and three cations by 2 (3 Na(+), 3 K(+), and mixtures) as well as mixed proton-metallic cation complexes of both were observed. The K(+)/Na(+) cation-binding selectivity of 18-crown-6 was studied by ESI-MS of a methanol solution, and the selectivity profile was favorably compared with data obtained previously by ion-selective electrode techniques in the same solvent.
    Language English
    Publishing date 1996-07-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 123490-0
    ISSN 1520-6904 ; 0022-3263
    ISSN (online) 1520-6904
    ISSN 0022-3263
    DOI 10.1021/jo960023p
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4473: Show issues Location:
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  4. Article ; Online: 3-[(1

    Xu, Rui / Wang, Keshi / Rizzi, James P / Huang, Heli / Grina, Jonas A / Schlachter, Stephen T / Wang, Bin / Wehn, Paul M / Yang, Hanbiao / Dixon, Darryl D / Czerwinski, Robert M / Du, Xinlin / Ged, Emily L / Han, Guangzhou / Tan, Huiling / Wong, Tai / Xie, Shanhai / Josey, John A / Wallace, Eli M

    Journal of medicinal chemistry

    2019  Volume 62, Issue 15, Page(s) 6876–6893

    Abstract: The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical activity in heavily pretreated advanced ccRCC patients. ... ...

    Abstract The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical activity in heavily pretreated advanced ccRCC patients. However, PT2385 was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism of PT2385 to its glucuronide metabolite. Herein we describe the discovery of second-generation HIF-2α inhibitor PT2977 with increased potency and improved pharmacokinetic profile achieved by reduction of phase 2 metabolism. Structural modification by changing the geminal difluoro group in PT2385 to a vicinal difluoro group resulted in enhanced potency, decreased lipophilicity, and significantly improved pharmacokinetic properties. In a phase 1 dose-escalation study, the clinical pharmacokinetics for PT2977 supports the hypothesis that attenuating the rate of glucuronidation would improve exposure and reduce variability in patients. Early evidence of clinical activity shows promise for PT2977 in the treatment of ccRCC.
    MeSH term(s) Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/metabolism ; Dogs ; Dose-Response Relationship, Drug ; Female ; Haplorhini ; Humans ; Indans/chemical synthesis ; Indans/pharmacology ; Indans/therapeutic use ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/metabolism ; Mice ; Mice, SCID ; Rats ; Sulfones/chemical synthesis ; Sulfones/pharmacology ; Sulfones/therapeutic use ; Treatment Outcome ; Xenograft Model Antitumor Assays/methods
    Chemical Substances Antineoplastic Agents ; Basic Helix-Loop-Helix Transcription Factors ; Indans ; PT2385 ; Sulfones ; endothelial PAS domain-containing protein 1 (1B37H0967P)
    Language English
    Publishing date 2019-07-08
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.9b00719
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Show issues Location:
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  5. Article ; Online: Design and Activity of Specific Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitors for the Treatment of Clear Cell Renal Cell Carcinoma: Discovery of Clinical Candidate ( S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1 H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385).

    Wehn, Paul M / Rizzi, James P / Dixon, Darryl D / Grina, Jonas A / Schlachter, Stephen T / Wang, Bin / Xu, Rui / Yang, Hanbiao / Du, Xinlin / Han, Guangzhou / Wang, Keshi / Cao, Zhaodan / Cheng, Tzuling / Czerwinski, Robert M / Goggin, Barry S / Huang, Heli / Halfmann, Megan M / Maddie, Melissa A / Morton, Emily L /
    Olive, Sarah R / Tan, Huiling / Xie, Shanhai / Wong, Tai / Josey, John A / Wallace, Eli M

    Journal of medicinal chemistry

    2018  Volume 61, Issue 21, Page(s) 9691–9721

    Abstract: HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of ... ...

    Abstract HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π*
    MeSH term(s) Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors ; Basic Helix-Loop-Helix Transcription Factors/chemistry ; Carcinoma, Renal Cell/pathology ; Cell Line, Tumor ; Dogs ; Drug Design ; Indans/chemistry ; Indans/pharmacokinetics ; Indans/pharmacology ; Kidney Neoplasms/pathology ; Mice ; Models, Molecular ; Protein Conformation ; Rats ; Structure-Activity Relationship ; Sulfones/chemistry ; Sulfones/pharmacokinetics ; Sulfones/pharmacology ; Tissue Distribution
    Chemical Substances Antineoplastic Agents ; Basic Helix-Loop-Helix Transcription Factors ; Indans ; PT2385 ; Sulfones ; endothelial PAS domain-containing protein 1 (1B37H0967P)
    Language English
    Publishing date 2018-10-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.8b01196
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma.

    Wallace, Eli M / Rizzi, James P / Han, Guangzhou / Wehn, Paul M / Cao, Zhaodan / Du, Xinlin / Cheng, Tzuling / Czerwinski, Robert M / Dixon, Darryl D / Goggin, Barry S / Grina, Jonas A / Halfmann, Megan M / Maddie, Melissa A / Olive, Sarah R / Schlachter, Stephen T / Tan, Huiling / Wang, Bin / Wang, Keshi / Xie, Shanhai /
    Xu, Rui / Yang, Hanbiao / Josey, John A

    Cancer research

    2016  Volume 76, Issue 18, Page(s) 5491–5500

    Abstract: More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia- ... ...

    Abstract More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. ©2016 AACR.
    MeSH term(s) Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors ; Calorimetry ; Carcinoma, Renal Cell/pathology ; Cell Line, Tumor ; Crystallography, X-Ray ; Humans ; Immunohistochemistry ; Immunoprecipitation ; Kidney Neoplasms/pathology ; Mice ; Mice, SCID ; Polymerase Chain Reaction ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Basic Helix-Loop-Helix Transcription Factors ; endothelial PAS domain-containing protein 1
    Language English
    Publishing date 2016-09-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-16-0473
    Database MEDical Literature Analysis and Retrieval System OnLINE

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