Mechanisms mediating arylidene-indolinones induced degradation: thoughts on "Discovery of a Drug-like, Natural Product-Inspired, DCAF11 Ligand Chemotype"

Abstract

In the recent issue of Nature Communications (2023 Nov 30;14(1):7908), Xue et. al. reported a very interesting and significant discovery of a possible DCAF11 ligand chemotype that could be used as the "warhead" to design bifunctional compounds for targeted degradation via engaging the E3 ligase DCAF11 1 (annotated as ref 1 hereafter). The discovery is of importance to the targeted protein degradation field and was inspired by previous reports suggesting that similar compounds may also engage the autophagosome protein LC3 for degradation and function as autophagy-tethering compounds (ATTECs) 2, 3, 4, 5, 6, 7, which seem to be inconsistent with ref 1. We think that the conclusions based on these data are not necessarily mutually exclusive. After performing additional experiments and analyses, we would like to discuss some possibilities explaining such discrepancies and make a few points of clarification.