Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling
Shuhui Lim, N. Boyer, Nicole Boo, Chunhui Huang, Gireedhar Venkatachalam, Yu‐Chi Juang, Michael Garrigou, Hung Yi Kristal Kaan, Ruchia Duggal, Khong Ming Peh, Ahmad Sadruddin, Pooja Gopal, Tsz Ying Yuen, Simon Ng, Srinivasaraghavan Kannan, Christopher J. Brown, Chandra Verma, Peter Orth, Andrea Peier, Lan Ge, Xiang Yu, Bhavana Bhatt, Feifei Chen, Erjia Wang, Nianyu Jason Li, Raymond J. Gonzales, Alexander Stoeck, Brian Henry, Tomi K. Sawyer, David P. Lane, Charles W. Johannes, Kaustav Biswas, Anthony W. Partridge
Abstract
assay, thus making this series unsuitable for advancement due to the potentially fatal consequences of mast cell degranulation. This observation should signal to researchers that cationic-mediated cell entry - an approach that has yet to succeed in the clinic despite a long history of attempts - carries significant therapy-limiting safety liabilities. Nonetheless, the cell-active molecules identified here validate a unique inhibitory epitope on KRAS and thus provide valuable molecular templates for the development of therapeutics that are desperately needed to address KRAS-driven cancers - some of the most treatment-resistant human malignancies.