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公开(公告)号:US12161625B2
公开(公告)日:2024-12-10
申请号:US18059806
申请日:2022-11-29
Applicant: Gilead Sciences, Inc.
Inventor: Jinfa Du , Joshua A. Kaplan , Thorsten A. Kirschberg , Tetsuya Kobayashi , Scott E. Lazerwith , Rick Andrew Lee , Jonathan William Medley , Michael L. Mitchell , Philip Anthony Morganelli , Hyung-Jung Pyun , Sophia L. Shevick , Neil H. Squires , William J. Watkins
IPC: A61K31/403 , A61K31/03 , A61K31/16 , A61K31/38 , A61K31/4192 , A61P31/20 , C07D487/04 , C07D519/00
Abstract: This application relates generally to certain substituted pyrrolizine compounds, and pharmaceutical compositions which inhibit HBV replication, and methods of making and using them.
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公开(公告)号:US20230212148A1
公开(公告)日:2023-07-06
申请号:US18061150
申请日:2022-12-02
Applicant: Gilead Sciences, Inc.
Inventor: Gediminas J. Brizgys , Chienhung Chou , Hang Chu , Julie Farand , Michael Graupe , Tezcan Guney , Darryl Kato , Jiayao Li , John O. Link , James B.C. Mack , Dong Min Mun , Scott D. Schroeder , William J. Watkins , Qiaoyin Wu , Jennifer R. Zhang
IPC: C07D401/14 , C07F9/6558 , A61K45/06
CPC classification number: C07D401/14 , C07F9/65583 , A61K45/06
Abstract: Background: HIV capsid (CA) is an emerging target for antiretroviral treatment PF-3450074 (P74) is a small-molecule CA binder that has been proposed to inhibit reverse transcription (RT) by accelerating HIV core uncoating. PF74 antiviral potency can depend on cyclophilin A (CypA) binding to CA in some cells and it shares a CA binding site with the host nuclear transport factor CPSF6, which restrict HIV infection when mislocalized to the cell cytoplasm. Here we further interrogate the mechanism of action (MOA) for PF74 in human T cells and clarify its potential dependence on CypA and CPSF6.
Methodology: HIV reporter viruses were produced in HEK293T cells and used to infect MT2 cells and primary CD4+ T cells to determine the antiviral effect of PF74. Compound exposure was controlled by staggered addition and cell washing at various times post-infection. DNA products of infection were analyzed by qPCR. CypA and CPSF6 levels were varied in MT2 cells by overexpression and shRNA knockdown. CA (P90A, N74D) and CPSF6 (FG50,AA) mutations were used to eliminate CypA or CPSF6 binding to the viral capsid. CPSF6 binding to CA was tested using a CA-NO pull down assay.
Results: PF74 efficiently inhibited late (EC50=795 nM) and early (EC50=264 nM) post-entry stages of HIV-1 replication in single-round infectivity assays and stabilized CA-NC polymers in vitro. Stable CypA knockdown or mutation of the CypA binding site of CA (P90A) had no effect on HIV infectivity or PF74 antiviral potency in T cells. CypA-independence of PF74 MOA was confirmed in PBMCs using HIV isolates unable to bind CypA due to CA polymorphisms. Drug washout studies showed that at high concentrations (100× EC50), PF74 inactivates cell-free virus via core disassembly and also acts concomitant with the RT step in infected cells. At 10× EC50, however, PF74 acted post-RT and was not virucidal, suggesting antiviral mechanism(s) beyond capsid destabilization. In time-of-addition studies, PF74 (10× EC50) remained active when added after RT but before vDNA integration, and normal levels of late-RT products but reduced 2-LTR circles were observed under these conditions. In contrast, reduced late-RT products were detected at higher compound concentrations. Although PF74 did compete with CPSF6 binding to CA in vitro, it remained active against the N740 mutant virus that does not bind CPSF6, suggesting a CPSF6-independent MOA.
Conclusions: Although PF74 can accelerate viral capsid disassembly at high concentrations, our results indicate that this compound primarly acts after the RT step, but prior to 2-LTR circle accumulation in human T cells, via a CypA- and CPSF6-independent MOA. We propose that by directly stabilizing the viral capsid at lower drug concentrations, PF74 may interfere with nuclear targeting of the pre-integration complex.-
公开(公告)号:US11555029B2
公开(公告)日:2023-01-17
申请号:US16891880
申请日:2020-06-03
Applicant: Gilead Sciences, Inc.
Inventor: Evangelos Aktoudianakis , Aesop Cho , Zhimin Du , Michael Graupe , Lateshkumar Thakorlal Lad , Paulo A. Machicao Tello , Jonathan William Medley , Samuel E. Metobo , Prasenjit Kumar Mukherjee , Devan Naduthambi , Eric Q. Parkhill , Barton W. Phillips , Scott Preston Simonovich , Neil H. Squires , Peiyuan Wang , William J. Watkins , Jie Xu , Kin Shing Yang , Christopher Allen Ziebenhaus
IPC: C07D403/14 , A61P31/20 , A61P35/02 , A61K31/496 , C07D519/00 , C07D241/20 , C07D487/10 , C07D405/14 , C07D487/08 , A61K31/497 , C07D491/107 , C07D241/18 , A61P35/00 , C07K16/28
Abstract: Compounds of Formula (I), methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.
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公开(公告)号:US20220340535A1
公开(公告)日:2022-10-27
申请号:US17171201
申请日:2021-02-09
Applicant: Gilead Sciences, Inc.
Inventor: Hang Chu , Juan A. Guerrero , Anna E. Hurtley , Tae H. Hwang , Lan Jiang , Darryl Kato , Tetsuya Kobayashi , John E. Knox , Scott E. Lazerwith , Xiaofen Li , David W. Lin , Jonathan W. Medley , Michael L. Mitchell , Devan Naduthambi , Zachary Newby , Neil H. Squires , Vickie H. Tsui , Chandrasekar Venkataramani , William J. Watkins , Hong Yang
IPC: C07D267/20 , C07D413/12 , C07D413/14 , C07D417/12 , C07D471/04 , C07D487/04 , C07D498/04
Abstract: The present disclosure generally relates to compounds and pharmaceutical compositions that may be used in methods of treating cancer.
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公开(公告)号:US20210053946A1
公开(公告)日:2021-02-25
申请号:US16891880
申请日:2020-06-03
Applicant: Gilead Sciences, Inc.
Inventor: Evangelos Aktoudianakis , Aesop Cho , Zhimin Du , Michael Graupe , Lateshkumar Thakorlal Lad , Paulo A. Machicao Tello , Jonathan William Medley , Samuel E. Metobo , Prasenjit Kumar Mukherjee , Devan Naduthambi , Eric Q. Parkhill , Barton W. Phillips , Scott Preston Simonovich , Neil H. Squires , Peiyuan Wang , William J. Watkins , Jie Xu , Kin Shing Yang , Christopher Allen Ziebenhaus
IPC: C07D403/14 , A61P31/20 , A61P35/02 , A61K31/496 , C07D519/00 , C07D241/20 , C07D487/10 , C07D405/14 , C07D487/08 , A61K31/497 , C07D491/107 , C07D241/18 , A61P35/00
Abstract: Compounds of Formula (I), methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.
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公开(公告)号:US10899735B2
公开(公告)日:2021-01-26
申请号:US16388517
申请日:2019-04-18
Applicant: Gilead Sciences, Inc
Inventor: Evangelos Aktoudianakis , Aesop Cho , Zhimin Du , Michael Graupe , Lateshkumar Thakorlal Lad , Paulo A. Machicao Tello , Jonathan William Medley , Samuel E. Metobo , Prasenjit Kumar Mukherjee , Devan Naduthambi , Eric Q. Parkhill , Barton W. Phillips , Scott Preston Simonovich , Neil H. Squires , Peiyuan Wang , William J. Watkins , Jie Xu , Kin Shing Yang , Christopher Allen Ziebenhaus
IPC: C07D401/10 , A61K31/444 , C07D401/04 , C07D401/12 , C07D401/14 , C07D487/10 , C07D519/00 , C07K16/28
Abstract: Compounds and methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.
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公开(公告)号:US10316017B2
公开(公告)日:2019-06-11
申请号:US15697755
申请日:2017-09-07
Applicant: Gilead Sciences, Inc.
Inventor: Elizabeth M. Bacon , Gayatri Balan , Chien-Hung Chou , Christopher T. Clark , Jeromy J. Cottell , Musong Kim , Thorsten A. Kirschberg , John O. Link , Gary Phillips , Scott D. Schroeder , Neil H. Squires , Kirk L. Stevens , James G. Taylor , William J. Watkins , Nathan E. Wright , Sheila M. Zipfel
IPC: C07D401/12 , C07D453/02 , C07D417/14 , C07D413/14 , C07D413/12 , C07D409/14 , C07D405/14 , C07D401/14 , C07F7/08
Abstract: The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) and methods of use and manufacture thereof.
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公开(公告)号:US10259811B2
公开(公告)日:2019-04-16
申请号:US16044054
申请日:2018-07-24
Applicant: Gilead Sciences, Inc.
Inventor: Zhimin Du , Juan Arnaldo Guerrero , Joshua Aaron Kaplan , John Edward Knox, Jr. , Devan Naduthambi , Barton W. Phillips , Chandrasekar Venkataramani , Peiyuan Wang , William J. Watkins , Jeff Zablocki
IPC: C07D471/04 , C07D519/00 , C07D473/00 , C07D487/04
Abstract: Compounds having the following formula (I) and methods of their use and preparation are disclosed:
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公开(公告)号:US10092563B2
公开(公告)日:2018-10-09
申请号:US14735254
申请日:2015-06-10
Applicant: Gilead Sciences, Inc.
Inventor: Shaopei Cai , Zhimin Du , Joshua Kaplan , Jennifer A. Loyer-Drew , Devan Naduthambi , Barton W. Phillips , Gary Phillips , Joshua Van Veldhuizen , William J. Watkins , Suet Chung Yeung
IPC: A61K31/496 , C07D239/04 , C07D239/80 , C07D401/14 , C07D413/14 , C07D407/14 , C07D487/04 , C07D239/90 , C07D471/04 , C07D491/048 , C07D495/04 , C07D513/04 , C07D403/14 , C07D405/14
Abstract: The present application provides the compounds of formula (J), or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, wherein W, B, n, m, A′, R1, R2, and R3 are described herein. The compounds are inhibitors to the activities of phosphatidylinositol 3-kinase (PI3K) and are useful for treating conditions mediated by one or more PI3K isoforms. The present application further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts, isomers, tautomer, or mixture thereof, and methods of using these compounds and compositions for treating conditions mediated by one or more PI3K isoforms.
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公开(公告)号:US10040781B2
公开(公告)日:2018-08-07
申请号:US14863108
申请日:2015-09-23
Applicant: Gilead Sciences, Inc.
Inventor: Zhimin Du , Juan A. Guerrero , Joshua A. Kaplan , John E. Knox, Jr. , Jennifer R. Lo , Scott A. Mitchell , Devan Naduthambi , Barton W. Phillips , Chandrasekar Venkataramani , Peiyuan Wang , William J. Watkins , Zhongdong Zhao
IPC: C07D405/12 , C07D403/12 , C07D401/14 , C07D405/14 , C07D413/14 , C07D409/14 , C07D417/14 , C07D471/08 , C07D471/10 , C07D487/04 , C07D491/113 , C07D498/04 , C07D403/14 , C07D491/107 , A61K31/53 , A61K31/5377 , A61K31/5383 , A61K31/541
Abstract: Compounds having the following formula (I) and methods of their use and preparation are disclosed:
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