Patent landscape of inhibitors and PROTACs of the anti-apoptotic BCL-2 family proteins.
Patent landscape of inhibitors and PROTACs of the anti-apoptotic BCL-2 family proteins.
复制标题
抗凋亡 BCL-2 家族蛋白抑制剂和 PROTAC 的专利情况。
DOI：
10.1080/13543776.2022.2116311
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发表时间：
2022-09
影响因子：
6.6
通讯作者：
Zheng, Guangrong
中科院分区：
文献类型：
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作者：
Pal, Pratik;Zhang, Peiyi;Poddar, Saikat K.;Zheng, Guangrong
抗凋亡BCL-2家族蛋白，如BCL-2、BCL-XL和MCL-1，是极好的癌症治疗靶点。2016年FDA批准BCL-2选择性抑制剂venetoclax，验证了用BH 3模拟小分子抑制剂靶向这些蛋白质的策略。本综述概述了2016年至2021年期间的专利文献，涵盖抗凋亡BCL-2蛋白的抑制剂和PROTAC。自从FDA批准venetoclax以来，已经做出了巨大的努力来开发具有改进药物特性的类似物。这些活动可能会在未来几年产生新的药物。MCL-1抑制剂也取得了重大进展，多种化合物进入临床试验。然而，MCL-1抑制可能对正常组织尤其是心脏造成靶向毒性。BCL-XL抑制剂也存在类似的问题，这会导致靶向血小板毒性。为了克服这个问题，已经应用了几种策略，包括前药、基于树枝状聚合物的药物递送、抗体-药物缀合物（ADC）和蛋白水解靶向嵌合体（PROTAC）;令人惊讶的是，这些方法中的每一种都导致候选药物进入临床试验。我们设想像ADC和PROTAC这样的技术也可以用于增加MCL-1抑制剂的治疗指数。
The anti-apoptotic BCL-2 family proteins, such as BCL-2, BCL-XL, and MCL-1, are excellent cancer therapeutic targets. The FDA approval of BCL-2 selective inhibitor venetoclax in 2016 validated the strategy of targeting these proteins with BH3 mimetic small molecule inhibitors. This review provides an overview of the patent literature between 2016 and 2021 covering inhibitors and PROTACs of the anti-apoptotic BCL-2 proteins. Since the FDA approval of venetoclax, tremendous efforts have been made to develop its analogues with improved drug properties. These activities will likely result in new drugs in coming years. Significant progress on MCL-1 inhibitors has also been made, with multiple compounds entering clinical trials. However, MCL-1 inhibition could cause on-target toxicity to normal tissues especially the heart. Similar issue exists with BCL-XL inhibitors, which cause on-target platelet toxicity. To overcome this issue, several strategies have been applied, including prodrug, dendrimer-based drug delivery, antibody-drug conjugate (ADC), and proteolysis targeting chimera (PROTAC); and amazingly, each of these approaches has resulted in a drug candidate entering clinical trials. We envision technologies like ADC and PROTAC could also be utilized to increase the therapeutic index of MCL-1 inhibitors.
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影响因子：
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作者：
Casara P;Davidson J;Claperon A;Le Toumelin-Braizat G;Vogler M;Bruno A;Chanrion M;Lysiak-Auvity G;Le Diguarher T;Starck JB;Chen I;Whitehead N;Graham C;Matassova N;Dokurno P;Pedder C;Wang Y;Qiu S;Girard AM;Schneider E;Gravé F;Studeny A;Guasconi G;Rocchetti F;Maïga S;Henlin JM;Colland F;Kraus-Berthier L;Le Gouill S;Dyer MJS;Hubbard R;Wood M;Amiot M;Cohen GM;Hickman JA;Morris E;Murray J;Geneste O
通讯作者：
Geneste O
影响因子：
6.6
作者：
Benowitz, Andrew B.;Jones, Katherine L.;Harling, John D.
通讯作者：
Harling, John D.
影响因子：
2.6
作者：
Bose P;Gandhi V;Konopleva M
通讯作者：
Konopleva M
影响因子：
28.2
作者：
Caenepeel, Sean;Brown, Sean P.;Hughes, Paul E.
通讯作者：
Hughes, Paul E.
DOI：
10.1038/s41573-021-00371-6
发表时间：
2022-03
期刊：
Nature reviews. Drug discovery
影响因子：
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作者：
Békés M;Langley DR;Crews CM
通讯作者：
Crews CM