Discovery ofaNovel 1,4-Benzodiazepine Derivativeas a Highly Selective ANXA3 Degrader for the Treatment of Triple-NegativeBreast Cancer

Annexin A3 has been demonstrated to be a key pathogenic protein in the occurrence and development of triple-negative breast cancer (TNBC); its overexpression in TNBC cells can promote the proliferation, migration, and drug resistance of TNBC. Previously, we reported the first ANXA3 degrader, (<i>R</i>)<b>-SL18</b>, with potent anti-TNBC effects, albeit with moderate ANXA3 binding affinity leading to off-target effects and relatively poor degradation selectivity of family proteins. To obtain molecules with stronger binding with ANXA3 and lower toxicity, we performed further structural optimization of (<i>R</i>)<i>-</i><b>SL18</b> to explore structure–activity relationships for a series of 1,4-benzodiazepines. Among them, compound <b>18a5</b> exhibited a 14-fold increase in ANXA3 binding activity, along with better cancer cell inhibition and functional activity. In particular, <b>18a5</b> showed more desirable ANXA3 selective degradation than (<i>R</i>)-<b>SL18</b> and displayed excellent inhibitory effect in a TNBC tumor xenograft model (TGI = 96%). Collectively, <b>18a5</b> proved to be a promising lead compound to treat TNBC through the degradation of ANXA3.