Organic ylides, defined by adjacent oppositely charged centers, are virtually absent from the pharmacopeia due to long-standing concerns over instability and reactivity under physiological conditions. Within this class, N-iminopyridinium ylides have remained unexplored. Herein, we report an efficient two-step synthesis of tetracyclic compounds incorporating this scaffold and demonstrate their function as chemically stable pharmacophores for targeted protein degradation. Lead compound 4p exhibited potent binding to the bromodomains of SMARCA2 and SMARCA4 while demonstrating remarkable stability in aqueous buffer and cell culture media, along with favorable cell permeability. Computational studies, together with head-to-head comparison against the corresponding amide analog, confirmed that the ylide moiety is indispensable for activity. Building on this scaffold, PROTAC 14 induced robust degradation of SMARCA2 and PBRM1 in SMARCA4 mutant cancer cells, suppressed cell proliferation, displayed favorable pharmacokinetics in rodents, and achieved significant antitumor efficacy in a xenograft model. Collectively, these findings establish the N-iminopyridinium ylide as a chemically stable, biocompatible, and pharmacologically tractable scaffold for designing bioactive ligands and degraders. More broadly, they position organic ylides as a previously untapped class of pharmacophores for drug discovery, thereby expanding the chemical space for targeted protein degradation.
Zhang et al. (Thu,) studied this question.