Frontiers in Medicinal Chemistry

Volume: 1

Protein Farnesyltransferase Inhibitors

Author(s): Semiramis Ayral-Kaloustian and Edward J. Salaski

Pp: 97-128 (32)

DOI: 10.2174/978160805204210401010097

* (Excluding Mailing and Handling)

Abstract

Specific mutations in the ras gene impair the guanosine triphophatase (GTPase) activity of Ras proteins, which play a fundamental role in the signaling cascade, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not anchor onto cell membranes and cannot induce this transformation. Posttranslational modification and plasma membrane association of mutant Ras is necessary for this transforming activity. Since its identification, the enzyme protein farnesyltransferase (FTase) that catalyzes the first and essential step of the three Ras processing steps has emerged as the most promising target for therapeutic intervention. FTase has been implicated as a potential target in inhibiting the prenylation of a variety of proteins, thus in controlling varied disease states (e.g. cancer, neurofibromatosis, restenosis, viral hepatitis, bone resorption, parasitic infections, corneal inflammations, and diabetes) associated with prenyl modifications of Ras and other proteins. Furthermore, it has been suggested that FTase inhibitors indirectly help in inhibiting tumors via suppression of angiogenesis and induction of apoptosis. Major milestones have been achieved with small-molecule FTase inhibitors that show efficacy without toxicity in vitro, as well as in mouse models bearing ras-dependent tumors. With the determination of the crystal structure of mammalian FTase, existent leads have been fine-tuned and new potent molecules of diverse structural classes have been designed. Extensive in vitro and in vivo studies with these inhibitors have revealed the complexities of the signaling cascade involving FTase, and shed more light on possible modes of tumor inhibition, without providing a clear-cut mechanism of action. A few of these molecules are currently in the clinic, with at least three drug candidates in Phase II studies and two in Phase III. This article will review the progress that has been reported with FTase inhibitors in drug discovery and in the clinic.

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      • 11. app/Models/ContentAccess.php:647
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      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51399716 and j.to_ip >=51399716 )) and ((j.from_date <= 1739834602 and j.to_date >= 1739834602 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2269) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51399716 and j.to_ip >=51399716 )) and ((j.from_date <= 1739834602 and j.to_date >= 1739834602 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2269) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 51399716 and j.to_ip >=51399716 )) and ((j.from_date <= 1739834602 and j.to_date >= 1739834602 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 2269)
      790μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 948 and `b`.`banner_from_date` <= 1739834602 and `b`.`banner_to_date` >= 1739834602 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.09msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 948
      • 3: 1739834602
      • 4: 1739834602
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='396a27d087754cb55c28128e5cce95d4'
      210μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Keywords
    1Keywords.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        NE5EbnapS5fLyYyBQNO5XwrjcigRz5fmoJBoWfjj
        uc_cart_id
        396a27d087754cb55c28128e5cce95d4
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2269" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/2269
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IlZmSjBzVVltL0Y4UjFoQkFnN0dtamc9PSIsInZhbHVlIjoiVTFBNlhDMit3US8xNCtYcW41M0k3RWJMZXF0c1JIaDY1NnI5NU1MbTd4RT0iLCJtYWMiOiJkYTkwOTAxMWQ3ODEwZmFmYWJhYTA1ZTJmZDQxNDlmMDRmZTJkYWJiYjUwOGI5YWE0N2ZlMWQyNDJmMDcwMzVlIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IlZmSjBzVVltL0Y4UjFoQkFnN0dtamc9PSIsInZhbHVlIjoiVTFBNlhDMit3US8xNCtYcW41M0k3RWJMZXF0c1JIaDY1NnI5NU1MbTd4RT0iLCJtYWMiOiJkYTkwOTAxMWQ3ODEw" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Mon, 17 Feb 2025 23:23:22 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Im03aXZQaGJzSHg0V001ZW00RUdXYlE9PSIsInZhbHVlIjoiVkt4SVlxMFZxWTRCVEZTb3IrUnNmRlVIT0htUFV5enoxNG1LWGt0YmxUYmpmR3J4eHhKWXV5aGlaY09YbXRGdzcxK0FrYUV3NmgvbjhkclNSTkMxZHFlMzFMcHIzdjQ3bnR2cUJIQXJkeW9wSGV1eGtnZEw4UDl1eU9IM0tBcWsiLCJtYWMiOiJhNjQwY2NmNWZjMGZjYjc0MWQyNWQyOWI3Mjk3NjkzMmM4ZGIyNTg2ZDY1ODNjYmFhN2I0NzJkMmU0OTJkMmUxIiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 11:23:22 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6Im03aXZQaGJzSHg0V001ZW00RUdXYlE9PSIsInZhbHVlIjoiVkt4SVlxMFZxWTRCVEZTb3IrUnNmRlVIT0htUFV5enoxNG1LWGt0YmxUYmpmR3J4eHhKWXV5aGlaY09YbXRGdzcxK0FrY" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlRxdW5yN2tEbVdGbDE1SkV1cWR0TGc9PSIsInZhbHVlIjoiRHE4N2tSNHNhcjQxOSsrMGREV1p1cE9GenZ0VlE3dVY5VGpLSEVOWHFvUXlNdU0yOEZBN2NKUDBvODlEQ3BNK1JPYy9kdFRPNllHWDBZcjlKd3NBUzNQWkl6U29LQkh1WTU0QTBnUzFpd0R0TXgzRG9wTHJhdHBkZWUxT0xIK2EiLCJtYWMiOiJkNTUzYzk2ZjVlZTQxZWI1YjQ5YTgzYTBlYWZjN2Y1MzRjMDhiMTkwNDE4YzJmODllN2RhZGUwY2E3MDM4YjJkIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IlRxdW5yN2tEbVdGbDE1SkV1cWR0TGc9PSIsInZhbHVlIjoiRHE4N2tSNHNhcjQxOSsrMGREV1p1cE9GenZ0VlE3dVY5VGpLSEVOWHFvUXlNdU0yOEZBN2NKUDB" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Im03aXZQaGJzSHg0V001ZW00RUdXYlE9PSIsInZhbHVlIjoiVkt4SVlxMFZxWTRCVEZTb3IrUnNmRlVIT0htUFV5enoxNG1LWGt0YmxUYmpmR3J4eHhKWXV5aGlaY09YbXRGdzcxK0FrYUV3NmgvbjhkclNSTkMxZHFlMzFMcHIzdjQ3bnR2cUJIQXJkeW9wSGV1eGtnZEw4UDl1eU9IM0tBcWsiLCJtYWMiOiJhNjQwY2NmNWZjMGZjYjc0MWQyNWQyOWI3Mjk3NjkzMmM4ZGIyNTg2ZDY1ODNjYmFhN2I0NzJkMmU0OTJkMmUxIiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 11:23:22 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6Im03aXZQaGJzSHg0V001ZW00RUdXYlE9PSIsInZhbHVlIjoiVkt4SVlxMFZxWTRCVEZTb3IrUnNmRlVIT0htUFV5enoxNG1LWGt0YmxUYmpmR3J4eHhKWXV5aGlaY09YbXRGdzcxK0FrY" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlRxdW5yN2tEbVdGbDE1SkV1cWR0TGc9PSIsInZhbHVlIjoiRHE4N2tSNHNhcjQxOSsrMGREV1p1cE9GenZ0VlE3dVY5VGpLSEVOWHFvUXlNdU0yOEZBN2NKUDBvODlEQ3BNK1JPYy9kdFRPNllHWDBZcjlKd3NBUzNQWkl6U29LQkh1WTU0QTBnUzFpd0R0TXgzRG9wTHJhdHBkZWUxT0xIK2EiLCJtYWMiOiJkNTUzYzk2ZjVlZTQxZWI1YjQ5YTgzYTBlYWZjN2Y1MzRjMDhiMTkwNDE4YzJmODllN2RhZGUwY2E3MDM4YjJkIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IlRxdW5yN2tEbVdGbDE1SkV1cWR0TGc9PSIsInZhbHVlIjoiRHE4N2tSNHNhcjQxOSsrMGREV1p1cE9GenZ0VlE3dVY5VGpLSEVOWHFvUXlNdU0yOEZBN2NKUDB" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "NE5EbnapS5fLyYyBQNO5XwrjcigRz5fmoJBoWfjj" "uc_cart_id" => "396a27d087754cb55c28128e5cce95d4" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/2269" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:23:22GET/chapter/2269112193