Abstract C137: Tumor-selective, chaperone-mediated targeting of ERK5 (MAPK7)

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Abstract Extracellular signal-regulated kinase 5 (ERK5 or MAPK7) belongs to the mitogen-activated protein kinase family and has been associated with a wide range of cellular functions, including cell proliferation, migration, differentiation and survival. ERK5 has also been implicated in the onset and progression of several types of cancer. Importantly, studies comparing pharmacological inhibition versus genetic deletion or knockdown of ERK5 have revealed that it also possesses kinase activity-independent functions, suggesting that an ERK5 protein degrader approach may be required to completely block all ERK5-regulated signaling. To this end, we have explored applying Chaperone-mediated Protein Degradation (CHAMP) technology to target ERK5 protein. CHAMPs are heterobifunctional small molecules that mediate protein degradation by inducing proximity between a target protein and the HSP90 chaperone complex, resulting in target ubiquitination and degradation by the proteasome. Due to HSP90 being highly activated in cancer cells, CHAMPs also preferentially accumulate in tumors relative to normal tissues, resulting in an improved therapeutic index versus typical inhibitors. In order to chemically induce ERK5 degradation, CHAMP compounds were synthesized by covalently coupling ERK5- and HSP90-binding moieties through a short linker. CHAMP treatment of cancer cell lines resulted in formation of an ERK5-CHAMP-HSP90 ternary complex and subsequent proteasome-dependent ERK5 degradation. This in turn resulted in inhibition of ERK5 downstream signaling, leading to cell growth inhibition, cell cycle arrest and apoptosis in a panel of cancer cell lines. Further, in mouse xenograft models, CHAMPs displayed prolonged pharmacokinetics in tumors relative to plasma and normal tissues and strongly inhibited tumor growth at tolerated doses. Based on these findings, ERK5-targeted CHAMPs represents a promising new approach to disrupt the entire function of ERK5 for the of treatment cancer. Citation Format: Kevin P Foley, Xiangcai Yang, Wei Yin, Mengmeng Xu, Mingkai Wang, Qinglin Ding, Yan Dai, Haoxin Zhou, Ignazia Tusa, Alessio Menconi, Zoe Lombardi, Alessandro Tubita, Thomas L Prince, Guoqiang Wang, Elisabetta Rovida, Weiwen Ying. Tumor-selective, chaperone-mediated targeting of ERK5 (MAPK7) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C137.