Mutant-selective degradation by BRAF-targeting PROTACs.
Mutant-selective degradation by BRAF-targeting PROTACs.
复制标题
DOI：
10.1038/s41467-021-21159-7
复制
发表时间：
2021-02-10
影响因子：
16.6
通讯作者：
Crews CM
中科院分区：
文献类型：
--
作者：
Alabi S;Jaime-Figueroa S;Yao Z;Gao Y;Hines J;Samarasinghe KTG;Vogt L;Rosen N;Crews CM
已经在患者中鉴定出超过300种BRAF错义突变，但目前批准的药物仅针对V600突变体。此外，获得性耐药性不可避免地出现，主要是由于RAF病变阻止了当前治疗对BRAF V600的抑制。因此，需要靶向激活的BRAF的其他机制的新疗法。在这项研究中，我们使用蛋白水解靶向嵌合体（PROTAC）技术，该技术促进新底物的泛素化和降解，以解决基于BRAF的疗法的局限性。使用基于维罗非尼的PROTAC，我们实现了所有类别的BRAF突变体的低纳摩尔降解，但避免了WT RAF家族成员的降解。我们领先的PROTAC在抑制癌细胞生长方面优于vemurafenib，并在2类BRAF异种移植模型中显示出体内疗效。机制研究表明，BRAFWT是由于其静止的失活构象，在细胞中形成三元复合物弱，幸免于难，激活BRAFWT敏感的降解。这项研究强调了通过靶向突变BRAF驱动的癌症同时保留BRAFWT的基于降解的方法可实现的选择性程度，提供了一种扩大治疗窗口的抗肿瘤药物模式。在癌症患者中已经发现了数百种BRAF突变，但目前批准的药物仅针对BRAF V600突变体。在这里，作者开发了一种基于vemurafenib的PROTAC，它诱导所有类型的BRAF突变体的降解，而不影响野生型RAF蛋白。
Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window. Hundreds of BRAF mutations have been identified in patients with cancer but currently approved drugs only target BRAF V600 mutants. Here, the authors develop a vemurafenib-based PROTAC that induces degradation of all classes of BRAF mutants without affecting wild-type RAF proteins.
登录
查看更多内容
影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
11.2
作者：
Hines J;Lartigue S;Dong H;Qian Y;Crews CM
通讯作者：
Crews CM
DOI：
10.1073/pnas.95.16.9214
发表时间：
1998-08-04
影响因子：
11.1
作者：
Cutler, RE;Stephens, RM;Morrison, DK
通讯作者：
Morrison, DK
影响因子：
11.2
作者：
Burslem, George M.;Schultz, Anna Reister;Crews, Craig M.
通讯作者：
Crews, Craig M.
影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM