Frontiers in Anti-Cancer Drug Discovery

Volume: 9

The Prospects of CDK Targeting and Clinical Application of CDK Inhibitors in Cancer

Author(s): Aditi Gangopadhyay and Aparna Gangopadhyay

Pp: 234-286 (53)

DOI: 10.2174/9781681087016118090008

* (Excluding Mailing and Handling)

Abstract

CDKs (Cyclin-Dependent Kinases) are protein kinases that regulate cell cycle progression. In cancer cells, which are characterised by unregulated proliferation, CDK expression and activity are often deregulated. CDKs are potential therapeutic targets in cancer therapy. However, the inhibition of CDKs is a complicated affair and has been the subject of drug discovery for decades. With the preclinical and clinical phases of CDK inhibitor discovery confronted by drug resistance, low selectivity, and the need for selective inhibitors, and the successful development of CDK inhibitors is challenging. The application of proper patient selection has shown promise in the identification of highly selective CDK inhibitors. Promising results from clinical studies have led to the rapid approval of CDK dual inhibitors by the FDA and EMA; clinical guidelines from the NCCN and ESMO advocate their use in advanced breast cancer in combination with aromatase inhibitors in hormone receptor positive patients. Rapidly evolving data indicate that dual CDK inhibitors may favorably modulate the immune microenvironment and thus may be good partners for checkpoint blockade. Although promising, dual inhibitors will not offer an ultimate cure and tumour cells will engineer a way around them. A key challenge to therapeutic application is determining appropriate biomarkers to identify patients who may benefit most. An area of concern, as with all targeted therapy, is the study of mechanisms of acquired resistance to these drugs. Defining the mechanisms of resistance will be critical for designing future strategies. The inhibition of CDKs thus presents a complicated yet promising line of anticancer therapy. After a brief introduction to the molecular biology of CDKs and CDK inhibition, the chapter will focus on the present status and future prospects of targeting CDKs for cancer therapy, taking lessons from the failures and success stories of clinical trials in CDK inhibition.


Keywords: Cancer, Cell cycle, Clinical guidelines, Clinical trials, Cyclins, CDK, CDK deregulation, CDK drug discovery, CDK inhibitors, CDK molecular biology.

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      • 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 <= 59769557 and j.to_ip >=59769557 )) and ((j.from_date <= 1740496860 and j.to_date >= 1740496860 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12787) 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 <= 59769557 and j.to_ip >=59769557 )) and ((j.from_date <= 1740496860 and j.to_date >= 1740496860 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12787) 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 <= 59769557 and j.to_ip >=59769557 )) and ((j.from_date <= 1740496860 and j.to_date >= 1740496860 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12787)
      540μsalphaeurekaselec_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` = 2632 and `b`.`banner_from_date` <= 1740496860 and `b`.`banner_to_date` >= 1740496860 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.39msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 2632
      • 3: 1740496860
      • 4: 1740496860
      • 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='8cebfc0102b2d3854d1c5e7070e6b615'
      250μsalphaeurekaselec_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\Keywords
    10Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        we8X2xMCA1RWohWcrrZqQBOagumZ60fLfSbp1KxP
        uc_cart_id
        8cebfc0102b2d3854d1c5e7070e6b615
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/12787" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/12787
        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=eyJpdiI6IlJWSTZkT2t0bXZieG56WndlL0JWTEE9PSIsInZhbHVlIjoiOEt5UFVySk9VaDVnRXZyazgvaFN2OUJTcXRwWE5ydDdubkRzZERPUkZGMD0iLCJtYWMiOiIyNDk2ZjU3NDM5YmE4N2I3MmU5ZGZiYjIzNzZiMmZjOGI4NzY3NzFlZTA5NzNiNjY4YmRmOGViMzk1NjY4YjE5IiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IlJWSTZkT2t0bXZieG56WndlL0JWTEE9PSIsInZhbHVlIjoiOEt5UFVySk9VaDVnRXZyazgvaFN2OUJTcXRwWE5ydDdubkRzZERPUkZGMD0iLCJtYWMiOiIyNDk2ZjU3NDM5YmE4" ] "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 => "Tue, 25 Feb 2025 15:21:00 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6InlRR3ZNbVJ3bzRJeEhqQkVKVUtQcnc9PSIsInZhbHVlIjoid0hJdjl6NUJ5elV2L1J2QUtheUZIZkhWUlRIMUdYVGxkUXJiYzZCd3FhcWlHOG9WUDRsNVBTc0JmRk11bmQ3ZWptSUp4OWhra0FYMmFDdDc2U3cxWkg5bnkwbEptdFNNUC9BbnllMTNmblhJSHVEWkJDMytaZjVLdGpQTFErRmkiLCJtYWMiOiI5NjkyYzA5MTVmMDRmM2NjZjljNTNjNzMwNDgzMjA2M2FlZDMzNzgwYTI4MTkxMGI5NjMzZGQ1NTMyODdiMDk3IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 03:21:00 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6InlRR3ZNbVJ3bzRJeEhqQkVKVUtQcnc9PSIsInZhbHVlIjoid0hJdjl6NUJ5elV2L1J2QUtheUZIZkhWUlRIMUdYVGxkUXJiYzZCd3FhcWlHOG9WUDRsNVBTc0JmRk11bmQ3ZWptSUp4O" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImtCNTFTeGcvL1MzYkFZRDVKcGxyNWc9PSIsInZhbHVlIjoiOWcxakx5SEg1OEhBVHI1TEFhaktmcWJucGloYk5CN1ROcVphZ0VVd3c3RSs3aE1FK0Nubit6VnJUVS8zc1loczZ0RG82elBldEpJak5BTjZiSzJhbFc2Q0dKcHRwUzl0OVEzaUEvRHV0Y0xBS2FFNlZVdC9HbnNGVlZ1dmtVWjkiLCJtYWMiOiI1NGY1YTdiNDYzYWJmZTRjMmZmMThmNDdkMjU2Nzc1YTgwMDNkZmZjZGE3MGYyOTkxM2RjMWEwMjFhODBlMjBjIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6ImtCNTFTeGcvL1MzYkFZRDVKcGxyNWc9PSIsInZhbHVlIjoiOWcxakx5SEg1OEhBVHI1TEFhaktmcWJucGloYk5CN1ROcVphZ0VVd3c3RSs3aE1FK0Nubit6VnJ" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6InlRR3ZNbVJ3bzRJeEhqQkVKVUtQcnc9PSIsInZhbHVlIjoid0hJdjl6NUJ5elV2L1J2QUtheUZIZkhWUlRIMUdYVGxkUXJiYzZCd3FhcWlHOG9WUDRsNVBTc0JmRk11bmQ3ZWptSUp4OWhra0FYMmFDdDc2U3cxWkg5bnkwbEptdFNNUC9BbnllMTNmblhJSHVEWkJDMytaZjVLdGpQTFErRmkiLCJtYWMiOiI5NjkyYzA5MTVmMDRmM2NjZjljNTNjNzMwNDgzMjA2M2FlZDMzNzgwYTI4MTkxMGI5NjMzZGQ1NTMyODdiMDk3IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 03:21:00 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6InlRR3ZNbVJ3bzRJeEhqQkVKVUtQcnc9PSIsInZhbHVlIjoid0hJdjl6NUJ5elV2L1J2QUtheUZIZkhWUlRIMUdYVGxkUXJiYzZCd3FhcWlHOG9WUDRsNVBTc0JmRk11bmQ3ZWptSUp4O" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImtCNTFTeGcvL1MzYkFZRDVKcGxyNWc9PSIsInZhbHVlIjoiOWcxakx5SEg1OEhBVHI1TEFhaktmcWJucGloYk5CN1ROcVphZ0VVd3c3RSs3aE1FK0Nubit6VnJUVS8zc1loczZ0RG82elBldEpJak5BTjZiSzJhbFc2Q0dKcHRwUzl0OVEzaUEvRHV0Y0xBS2FFNlZVdC9HbnNGVlZ1dmtVWjkiLCJtYWMiOiI1NGY1YTdiNDYzYWJmZTRjMmZmMThmNDdkMjU2Nzc1YTgwMDNkZmZjZGE3MGYyOTkxM2RjMWEwMjFhODBlMjBjIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6ImtCNTFTeGcvL1MzYkFZRDVKcGxyNWc9PSIsInZhbHVlIjoiOWcxakx5SEg1OEhBVHI1TEFhaktmcWJucGloYk5CN1ROcVphZ0VVd3c3RSs3aE1FK0Nubit6VnJ" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "we8X2xMCA1RWohWcrrZqQBOagumZ60fLfSbp1KxP" "uc_cart_id" => "8cebfc0102b2d3854d1c5e7070e6b615" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/12787" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:21:00GET/chapter/127871121912