Targeting cancer with small molecule pan-KRAS degraders

Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue[1][1]. However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand[2][2]. Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo . Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. ### Competing Interest Statement Johannes Popow, Andreas Gollner, Christiane Kofink, Gerhard Fischer, Melanie Wurm, Nikolai Mischerikow, Carina Hasenoehrl, Heribert Arnhof, Silvia Arce-Solano, Sammy Bell, Georg Boeck, Jale Karolyi-Oezguer, Theresa Klawatsch, Manfred Koegl, Roland Kousek, Barbara Kratochvil, Katrin Kropatsch, Arnel A. Lauber, Sabine Olt, Daniel Peter, Oliver Petermann, Vanessa Roessler, Peggy Stolt-Bergner, Patrick Strack, Eva Strauss, Jens Quant, Harald Weinstabl, Peter Ettmayer are current or former employees of Boehringer Ingelheim. A.C. is a scientific founder, shareholder and advisor of Amphista Therapeutics, a company that is developing targeted protein degradation therapeutic platforms. The Ciulli laboratory receives or has received sponsored research support from Almirall, Amgen, Amphista Therapeutics, Boehringer Ingelheim, Eisai, Merck KaaG, Nurix Therapeutics, Ono and Tocris-Biotechne. [1]: #ref-1 [2]: #ref-2