Targeting cancer with small-molecule pan-KRAS degraders.
Johannes PopowWilliam FarnabyAndreas GollnerChristiane KofinkGerhard FischerMelanie WurmDavid ZollmanAndre WijayaNikolai MischerikowCarina HasenoehrlPolina ProkofevaHeribert ArnhofSilvia Arce-SolanoSammy BellGeorg BoeckEmelyne DiersAileen B FrostJake Goodwin-TindallJale Karolyi-OezguerShakil KhanTheresa KlawatschManfred KoeglRoland KousekBarbara KratochvilKatrin KropatschArnel A LauberRoss McLennanSabine OltDaniel PeterOliver PetermannVanessa RoesslerPeggy Stolt-BergnerPatrick StrackEva StraussNicole TrainorVesna VetmaClaire WhitworthSiying ZhongJens QuantHarald WeinstablBernhard KusterPeter EttmayerAlessio CiulliPublished in: Science (New York, N.Y.) (2024)
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.