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  1. Article ; Online: Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy.

    Jackson, Jeffrey J / Shibuya, Grant M / Ravishankar, Buvana / Adusumilli, Lavanya / Bradford, Delia / Brockstedt, Dirk G / Bucher, Cyril / Bui, Minna / Cho, Cynthia / Colas, Christoph / Cutler, Gene / Dukes, Adrian / Han, Xinping / Hu, Dennis X / Jacobson, Scott / Kassner, Paul D / Katibah, George E / Ko, Michelle Yoo Min / Kolhatkar, Urvi /
    Leger, Paul R / Ma, Anqi / Marshall, Lisa / Maung, Jack / Ng, Andrew A / Okano, Akinori / Pookot, Deepa / Poon, Daniel / Ramana, Chandru / Reilly, Maureen K / Robles, Omar / Schwarz, Jacob B / Shakhmin, Anton A / Shunatona, Hunter P / Sreenivasan, Raashi / Tivitmahaisoon, Parcharee / Xu, Mengshu / Zaw, Thant / Wustrow, David J / Zibinsky, Mikhail

    Journal of medicinal chemistry

    2022  Volume 65, Issue 19, Page(s) 12895–12924

    Abstract: General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell- ... ...

    Abstract General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound
    MeSH term(s) Animals ; Heme ; Mice ; Mice, Knockout ; Myeloid-Derived Suppressor Cells ; Protein Serine-Threonine Kinases ; T-Lymphocytes/metabolism ; eIF-2 Kinase/metabolism
    Chemical Substances Heme (42VZT0U6YR) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
    Language English
    Publishing date 2022-09-20
    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/acs.jmedchem.2c00736
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity

    Ohol, Yamini M / Sun, Michael T / Cutler, Gene / Leger, Paul R / Hu, Dennis X / Biannic, Berenger / Rana, Payal / Cho, Cynthia / Jacobson, Scott / Wong, Steve T / Sanchez, Jerick / Shah, Niket / Pookot, Deepa / Abraham, Betty / Young, Kyle / Suthram, Silpa / Marshall, Lisa A / Bradford, Delia / Kozon, Nathan /
    Han, Xinping / Okano, Akinori / Maung, Jack / Colas, Christophe / Schwarz, Jacob / Wustrow, David / Brockstedt, Dirk G / Kassner, Paul D

    Molecular cancer therapeutics

    2020  Volume 19, Issue 10, Page(s) 1970–1980

    Abstract: The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. ...

    Abstract The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple
    MeSH term(s) Animals ; Cell Culture Techniques ; Cell Line, Tumor ; Female ; Humans ; Mice ; Models, Molecular ; Ubiquitin-Specific Peptidase 7/antagonists & inhibitors
    Chemical Substances Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12)
    Language English
    Publishing date 2020-08-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-20-0184
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.

    Leger, Paul R / Hu, Dennis X / Biannic, Berenger / Bui, Minna / Han, Xinping / Karbarz, Emily / Maung, Jack / Okano, Akinori / Osipov, Maksim / Shibuya, Grant M / Young, Kyle / Higgs, Christopher / Abraham, Betty / Bradford, Delia / Cho, Cynthia / Colas, Christophe / Jacobson, Scott / Ohol, Yamini M / Pookot, Deepa /
    Rana, Payal / Sanchez, Jerick / Shah, Niket / Sun, Michael / Wong, Steve / Brockstedt, Dirk G / Kassner, Paul D / Schwarz, Jacob B / Wustrow, David J

    Journal of medicinal chemistry

    2020  Volume 63, Issue 10, Page(s) 5398–5420

    Abstract: USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 ... ...

    Abstract USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound
    MeSH term(s) Administration, Oral ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/chemistry ; Cell Line, Tumor ; Crystallography, X-Ray/methods ; Drug Discovery/methods ; Humans ; Mice ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; Protein Structure, Tertiary ; Ubiquitin-Specific Peptidase 7/antagonists & inhibitors ; Ubiquitin-Specific Peptidase 7/chemistry ; Ubiquitin-Specific Peptidase 7/metabolism ; Xenograft Model Antitumor Assays/methods
    Chemical Substances Antineoplastic Agents ; USP7 protein, human (EC 3.4.19.12) ; Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12)
    Language English
    Publishing date 2020-05-06
    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/acs.jmedchem.0c00245
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Pharmacokinetic-pharmacodynamic modeling of tumor growth inhibition and biomarker modulation by the novel phosphatidylinositol 3-kinase inhibitor GDC-0941.

    Salphati, Laurent / Wong, Harvey / Belvin, Marcia / Bradford, Delia / Edgar, Kyle A / Prior, Wei Wei / Sampath, Deepak / Wallin, Jeffrey J

    Drug metabolism and disposition: the biological fate of chemicals

    2010  Volume 38, Issue 9, Page(s) 1436–1442

    Abstract: The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation, by activation or transforming mutations of the p110alpha subunit, is associated with the development of many cancers. 2-(1H- ... ...

    Abstract The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation, by activation or transforming mutations of the p110alpha subunit, is associated with the development of many cancers. 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) is a novel small molecule inhibitor of PI3K currently being evaluated in the clinic as an anticancer agent. The objectives of these studies were to characterize the relationships between GDC-0941 plasma concentrations and tumor reduction in MCF7.1 breast cancer xenografts and to evaluate the association between the tumor pharmacodynamic biomarker [phosphorylated (p) Akt and phosphorylated proline-rich Akt substrate of 40 kDa (pPRAS40)] responses and antitumor efficacy. MCF7.1 tumor-bearing mice were treated for up to 3 weeks with GDC-0941 at various doses (12.5-200 mg/kg) and dosing schedules (daily to weekly). An indirect response model fitted to tumor growth data indicated that the GDC-0941 plasma concentration required for tumor stasis was approximately 0.3 muM. The relationship between GDC-0941 plasma concentrations and inhibition of pAkt and pPRAS40 in tumor was also investigated after a single oral dose of 12.5, 50, or 150 mg/kg. An indirect response model was fitted to the inhibition of Akt and PRAS40 phosphorylation data and provided IC(50) estimates of 0.36 and 0.29 muM for pAkt and pPRAS40, respectively. The relationship between pAkt inhibition and tumor volume was further explored using an integrated pharmacokinetic biomarker tumor growth model, which showed that a pAkt inhibition of at least 30% was required to achieve stasis after GDC-0941 treatment of the MCF7.1 xenograft.
    MeSH term(s) Animals ; Biomarkers/metabolism ; Breast Neoplasms/pathology ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Female ; Humans ; Indazoles/pharmacokinetics ; Indazoles/pharmacology ; Mice ; Mice, Nude ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphorylation ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/pharmacology ; Sulfonamides/pharmacokinetics ; Sulfonamides/pharmacology
    Chemical Substances 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine ; Biomarkers ; Indazoles ; Protein Kinase Inhibitors ; Sulfonamides ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
    Language English
    Publishing date 2010-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 186795-7
    ISSN 1521-009X ; 0090-9556
    ISSN (online) 1521-009X
    ISSN 0090-9556
    DOI 10.1124/dmd.110.032912
    Database MEDical Literature Analysis and Retrieval System OnLINE

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