N‑Iminopyridinium Ylides as Chemically Stable Pharmacophores Enabling Targeted Degradation of SMARCA Proteins

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.