Abstract KRAS is one of the most frequently mutated oncogenes in cancer and is strongly associated with poor outcomes. For decades, it has been considered ‘undruggable’ because its surface lacks the deep binding pockets that small-molecule drugs can typically target and the very strong affinity to GTP/GDP makes it difficult for drugs to outcompete GTP. Recently, advances in structural biology led to the discovery of a regulatory allosteric pocket in the KRAS(G12D) mutant, which has opened the door to new therapeutic approaches for pancreatic cancer; unfortunately, single-agent allosteric inhibitors have shown little anti-cancer activity in patients. PROTACs (proteolysis-targeting chimeras) offer advantages over traditional inhibitors by degrading entire proteins independent of active sites or deep, hydrophobic binding pockets, making them attractive for hard-to-target proteins like KRAS. In our lab, we carried out an in silico screen and identified Pixantrone as the top hit for a possible KRAS-binding warhead. Based on this, we synthesized a library of PROTACs with various lengths of alkyl linkers tethering Pixantrone, the warhead targeting KRAS, to Pomalidomide, a well-known E3 ligase recruiter. We then assessed our PROTACs’ effectiveness in degrading KRAS and the corresponding effects in pancreatic cancer cell lines. In addition, we evaluated the MAPK signaling cascade, one of the KRAS downstream pathways. Evaluation of the Pixantrone-based PROTACs showed limited KRAS degradation and no significant effects on MAPK signaling or cell death, as assessed by cell viability and immunoblotting assays. These findings suggest that Pixantrone is not a suitable warhead for KRAS targeting. Moving forward, we are shifting our efforts toward validating other candidates from the screen, since PROTAC efficacy may be independent of kinase inhibition efficacy of the warhead alone. If successful, an improved PROTAC design may overcome the clinical ineffectiveness of the current generation of allosteric inhibitors. Citation Format: Fidelix Ayobami, Sai Kumar Samala, Ngoc Tuyet Tra, Geraldine V. Raja, Yuri Mackeyev, Sunil Krishnan. Design and optimization of small-molecule PROTACs targeting KRAS abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5170.
Ayobami et al. (2026) studied this question.