(R)-SL18 is a first-in-class, selective Annexin A3 (ANXA3) degrader, induces degradation of ANXA3 in MDA-MB-231 cells with DC50 value of 3.17 uM.
(R)-SL18 directly binds to ANXA3 (SPR Kd=0.58 uM) and increases its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity.
(R)-SL18 inhibits cell proliferation against TNBC cells with IC50 of 2.52 uM for MDA-MB-231 and 1.64 uM for MDA-MB-468, induces apoptosis.
(R)-SL18 showed certain selectivity for the anti-proliferative activity of ANXA3 high-expressing cells over ANXA3 low-expressing cells.
(R)-SL18 induced ANXA3 selective degradation mainly via the ubiquitin-proteasome system.
(R)-SL18 showed excellent family selectivity toward ANXA3 degradation (except ANXA6) in vitro.
(R)-SL18 (1-5 uM) inhibited the wnt/β-catenin signaling pathway in MDA-MB-231 cells.
(R)-SL18 (20 mg/kg, i.p.) suppressed tumor growth in TNBC PDX model.