LD-110 is a potent PROTAC degrader targeting LSD1 with a DC50 of 0.44 μM. It promotes LSD1 degradation via a ubiquitin-proteasome-dependent mechanism and enhances H3K4 dimethylation levels. By inducing apoptosis, LD-110 inhibits the growth and survival of various esophageal squamous cell carcinoma (ESCC) cell lines. It is applicable for research on esophageal squamous cell carcinoma.

LD-110 is a compound with a methylene linker consisting of four groups, demonstrating significant degradation activity at concentrations of 1, 3, and 10 μM, resulting in LSD1 protein degradation rates of 65%, 70%, and 84%, respectively. It exhibits strong binding affinity for LSD1 with a Kd of 6.2 μM within a range of 0.39-12.5 μM. Effective and dose-dependent degradation of LSD1 by LD-110 (0.1-30 μM, 6-72 hours) almost completely occurs within 48-72 hours, with DC 50 values of 0.44, 1.18, and 1.24 μM in KYSE-150, KYSE-30, and EC9706 ESCC cells, respectively. This degradation is highly specific, minimally impacting CoREST/HDAC1/HDAC2 levels, and significantly increasing H3K4me2 accumulation 2 to 7-fold. In KYSE-150 ESCC cells, LSD1 degradation induced by LD-110 (3 μM, 42 hours) can be effectively blocked by LSD1 inhibitors (LI-1), cereblon E3 ligand (Thalidomide), NAE inhibitor (MLN4924), and proteasome inhibitor (MG132). LD-110 (72 hours) potently inhibits ESCC cell growth, with IC 50 values of 3.94, 3.35, and 3.08 μM in KYSE-150, KYSE-30, and EC9706 cells, respectively. Additionally, LD-110 (3-10 μM, 10-14 days) efficiently suppresses proliferation of KYSE-30 and EC9706 esophageal squamous carcinoma cell lines， and induces dose-dependent early and late apoptosis, causing PARP and caspase-3 cleavage in KYSE-30 and EC9706 cells at 3-10 μM over 48 hours.

LD-110, administered via intraperitoneal injection at doses of 30 mg/kg and 100 mg/kg once daily for 24 days, exhibits potent dose-dependent antitumor activity in the KYSE-150 xenograft mouse model without causing significant toxicity.