Targeting cancer with small-molecule pan-KRAS degraders

被引：38

作者：

Popow, Johannes ^{[1
]}

Farnaby, William ^{[2
,3
]}

Gollner, Andreas ^{[1
]}

Kofink, Christiane ^{[1
]}

Fischer, Gerhard ^{[1
]}

Wurm, Melanie ^{[1
]}

Zollman, David ^{[2
,3
]}

Wijaya, Andre ^{[2
,3
]}

Mischerikow, Nikolai ^{[1
]}

Hasenoehrl, Carina ^{[1
]}

Prokofeva, Polina ^{[4
]}

Arnhof, Heribert ^{[1
]}

Arce-Solano, Silvia ^{[1
]}

Bell, Sammy ^{[5
]}

Boeck, Georg ^{[1
]}

Diers, Emelyne ^{[3
]}

Frost, Aileen B. ^{[2
,3
]}

Goodwin-Tindall, Jake ^{[3
]}

Karolyi-Oezguer, Jale ^{[1
]}

Khan, Shakil ^{[2
,3
]}

Klawatsch, Theresa ^{[1
]}

Koegl, Manfred ^{[1
]}

Kousek, Roland ^{[1
]}

Kratochvil, Barbara ^{[1
]}

Kropatsch, Katrin ^{[1
]}

Lauber, Arnel A. ^{[1
]}

Mclennan, Ross ^{[2
,3
]}

Olt, Sabine ^{[1
]}

Peter, Daniel ^{[1
]}

Petermann, Oliver ^{[1
]}

Roessler, Vanessa ^{[1
]}

Stolt-Bergner, Peggy ^{[1
]}

Strack, Patrick ^{[1
]}

Strauss, Eva ^{[1
]}

Trainor, Nicole ^{[3
]}

Vetma, Vesna ^{[2
,3
]}

Whitworth, Claire ^{[3
]}

Zhong, Siying ^{[3
]}

Quant, Jens ^{[1
]}

Weinstabl, Harald ^{[1
]}

Kuster, Bernhard ^{[4
]}

Ettmayer, Peter ^{[1
]}

Ciulli, Alessio ^{[2
,3
]}

机构：

[1] Boehringer Ingelheim RCV GmbH & Co KG, A-1221 Vienna, Austria

[2] Univ Dundee, Ctr Targeted Prot Degradat, Sch Life Sci, Dundee DD1 5JJ, Scotland

[3] Univ Dundee, Div Biol Chem & Drug Discovery, Sch Life Sci, James Black Ctr, Dundee DD1 5EH, Scotland

[4] Tech Univ Munich, Sch Life Sci, Prote & Bioanalyt, D-85354 Freising Weihenstephan, Germany

[5] Boehringer Ingelheim Pharmaceut, Ridgefield, CT 06877 USA

来源：

SCIENCE | 2024年 / 385卷 / 6715期

基金：

英国惠康基金;

关键词：

E3 UBIQUITIN LIGASE; POTENT; OPTIMIZATION; INHIBITOR;

D O I：

10.1126/science.adm8684

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

引用

页码：1338 / 1347

页数：10

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