NSD2/MMSET/WHSC1 Inhibitor

LLC0424 is a potent and selective cereblon-based PROTAC nuclear receptor-binding SET domain-containing 2 (NSD2) degrader. LLC0424 effectively degraded NSD2 with a DC₅₀ of 20 nM in RPMI-8402 cells. LLC0424 selectively induces NSD2 degradation in a cereblon- and proteasome-dependent fashion. (Blue: CRBN ligand (HY-14658), Black: linker (HY-40002); Pink: NSD2 inhibitor (HY-161575)).

LEM-14 is a potent and selective NSD2 inhibitor with an IC₅₀ of 132 µM. LEM-14 has very weak activitv against NSD1 and has no activity against NSD3. LEM-14 inhibits fibrotic gene expression in ND but not DIO BMDMs. LEM-14 combined with ionizing radiation (IR) enhances the apoptosis rate and reduces the colony-formation ability of CRC cells. LEM-14 exhibits enhanced anti-tumor efficacy in Balb/c nude mice bearing LoVo cell xenografts when combined with ionizing radiation. LEM-14 has the potential for the research of multiple myeloma and colorectal cancer.

W4275 (Compound 42) is a selective NSD2 inhibitor with oral activity, showing an IC₅₀ value of 17 nM. W4275 exhibits antiproliferative activity with an IC₅₀ of 230 nM against RS411 cells and significantly inhibits tumor growth in the RS411 tumor xenograft model. Pharmacokinetic analysis in mice demonstrates that W4275 has good oral bioavailability (F of 27.34%). W4275 holds promise for use in cancer research.

NSD2-PWWP1-IN-1 (compound 31) is a potent NSD2-PWWP1 inhibitor with an IC₅₀ value of 0.64 µM. NSD2-PWWP1-IN-1 has the potential for the research of cancer.

NSD2-IN-5 (Compound 198) is a SET domain-containing nuclear protein 2 (NSD2) inhibitor with an IC₅₀ value ranging from 0.001 μM to 0.01 μM. NSD2-IN-5 blocks the activity of NSD2, thereby regulating NSD2-mediated biological processes. NSD2-IN-5 can be used in the research of various cancers including breast cancer, cervical cancer, skin cancer, ovarian cancer, as well as pulmonary hypertension.

NSD2-PWWP1-IN-2 (compound 33) is a potent NSD2-PWWP1 inhibitor with an IC₅₀ value of 1.49 µM. NSD2-PWWP1-IN-2 has the potential for the research of cancer.

NSD2-PWWP1-IN-3 (compound 36) is a potent NSD2-PWWP1 inhibitor with an IC₅₀ value of 8.05 µM. NSD2-PWWP1-IN-3 has the potential for the research of cancer.

NSD-IN-5 is a nuclear receptor-binding SET domain (NSD) inhibitor with IC₅₀ values of 6 nM and < 1 nM against NSD1 and NSD2, respectively. NSD-IN-5 can be used in research related to multiple myeloma.

RK-0080552 (RK-552) is a NSD2 inhibitor with an IC₅₀ of 0.11 μM, and it exhibits selectivity over histone methyltransferases G9a (IC₅₀: 1.2 μM) and SET7/9 (IC₅₀: >50 μM). RK-0080552 functionally inhibits NSD2 histone methyltransferase activity, reduces the dimethylation level of histone H3 lysine 36, suppresses IRF4 transcription, induces apoptosis and triggers cell death. RK-0080552 inhibits the growth of xenograft tumors and prolongs host survival. RK-0080552 is available for the research of multiple myeloma.