Abstract 2158: Targeted intracellular disruption of oncogenic p53/HDM2 and p53/HDMX complexes underlies the therapeutic activity of a stapled peptide drug

Abstract

Abstract The first anti-cancer stapled peptide drug has now been advanced to clinical testing in relapsed human cancers that retain the expression of wild-type p53. A common mechanism for cancer cell suppression of wild-type p53 is overexpression of the negative regulators HDM2 and HDMX, which neutralize p53 through protein interaction. Selective HDM2 inhibitor molecules can effectively reactivate p53 in certain cancers, but the co-expression of HDMX can cause resistance, highlighting the need for dual HDM2/HDMX targeting. We previously developed stapled peptides modeled after the p53 transactivation domain to harness the natural propensity of this alpha-helical motif to engage both targets with high affinity and selectivity. Here, we demonstrate that ALRN-7041, a next-generation, clinical-grade stapled peptide, achieves time-dependent cellular uptake and nuclear localization without membrane perturbation, dose-dependently dissociates p53/HDM2 and p53/HDMX complexes as assessed by real-time protein interaction monitoring in live cells, and impairs the viability of cancer cells bearing wild-type p53 by inducing a surge in p53 protein level. Applying an unbiased statistical approach to determine which biophysical parameters dictate the cellular uptake of stapled peptides, we elucidated the design features of ALRN-7041 that confer intracellular access, providing a roadmap for generating cell-permeable stapled peptides with on mechanism cellular activity for clinical translation. We find that cancer cells exhibiting a signature of HDM2, HDMX, and wild-type p53 co-expression are strikingly susceptible to ALRN-7041, highlighting the therapeutic potential of dual HDM2/HDMX inhibition by a cell-penetrant stapled peptide in human cancer. Citation Format: Loren D. Walensky, Franziska Wachter, Ann Morgan, Marina Godes, Gregory Bird. Targeted intracellular disruption of oncogenic p53/HDM2 and p53/HDMX complexes underlies the therapeutic activity of a stapled peptide drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2158. doi:10.1158/1538-7445.AM2017-2158