Targeting cancer with small-molecule pan-KRAS degraders

Affiliations

• Boehringer Ingelheim RCV GmbH & Co KG, 1221 Vienna, Austria.
• Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee DD1 5JJ, UK.
• Division of Biological Chemistry and Drug Discovery, School of Life Sciences, James Black Centre, University of Dundee, Dundee DD1 5EH, UK.
• Proteomics and Bioanalytics, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany.
• Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, USA.

PMID:  39298590  DOI: 10.1126/science.adm8684

Abstract

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.

KRAS基因突变在癌症中高度普遍。然而，除了G12C突变抑制剂已临床应用外，其他等位基因的突变抑制剂依然没有好的候选物。我们设计了一种异双功能小分子PROTAC，通过对KRAS:PROTAC:VHL三元复合物的生物物理和结构研究，能够强效降解17种最常见KRAS致癌等位基因中的13种。与抑制相比，KRAS的降解在多种KRAS突变细胞系中表现出更深刻且持续的通路调控，能够杀死癌细胞，同时不影响没有KRAS基因异常的模型。在体内，KRAS致癌物的药理降解具有耐受性，并导致肿瘤缩小。这些发现共同揭示了通过小分子降解剂解决KRAS驱动的癌症的新途径。