Seldegamadlin

Seldegamadlin (KT-253) is a selective p53 stabilizer and a MDM2 PROTAC degrader (DC₅₀ = 0.4 nM). Seldegamadlin inhibits the proliferation of cancer cell RS4;11 with an IC₅₀ of 0.3 nM, arrests the cell cycle at G2/M phase, and induces apoptosis. Seldegamadlin upregulates p53 activity and overcomes the p53-MDM2 feedback loop. Seldegamadlin can be used for the study of hematologic and solid tumors, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). (Pink: ligand for target protein MDM2 ligand 4 (HY-170452); Black: linker (HY-W001478); Blue: ligand for E3 ligase cereblon (HY-163927))^[1][2][3][4]. In Vitro:KT-253 degrades MDM2 with subnanomolar potency at concentrations of 0.01 nmol/L, 0.1 nmol/L, 1 Seldegamadlin (KT-253) inhibits cell viability of RS4;11 ALL cells with an IC₅₀ of 0.3 nM. The strong growth inhibition by KT-253 Is driven by the recruitment of both CRBN and MDM2^[3].
Seldegamadlin (1.8 nM; 2-4 h) inhibits MDM2 protein expression in RS4;11 ALL cells^[3].
Seldegamadlin (20 nM; 2-8 h) induces selective and temporal upregulation of p53 and its downstream targets in RS4;11 ALL cells^[3].
Brief exposure to Seldegamadlin (1-1000 nM; 4 h) is sufficient to trigger apoptosis in RS4;11 ALL cells^[3].
Seldegamadlin (0.01-10000 nM; 8 h) shows potent induction of p53 transcriptional gene targets, including MDM2, GDF15, CDKN1A, GADD45A, TNFRSF10B, FAS, and BBC3^[3].
Seldegamadlin (1-1000 nM; 4 h) resultes in a significantly lower percentage of cells in S-phase in RS4;11 and MV4;11 cells^[3].
Seldegamadlin (1-10,000 nM; 48-96 h) is active in various solid tumor cell lines including neuroblastoma, rhabdoid, eye, bile duct, colorectal, liposarcoma, gastric sarcoma, bone, breast, lung, prostate, liver, brain, kidney, thyroid, bladder, skin, ovarian, cervical, endometrial/uterine, head and neck, non-Cancerous, pancreatic^[4].
In Vivo:Seldegamadlin (KT-253) (1 mg/kg-10 mg/kg; IV) achieves sustained tumor regression in RS4;11 (ALL) and MV-4-11 (AML) xenograft mice models^[1].
Seldegamadlin (1-3 mg/kg; IV; once) triggeres rapid apoptosis and sustaines tumor regression in RS4;11 tumor–bearing mice^[3].
In the MOLM-13 subcutaneous xenograft model, the combination of Seldegamadlin (3 mg/kg; intravenous injection; single dose) and Venetoclax (HY-15531) overcame Venetoclax resistance^[3].
Seldegamadlin (3-10 mg/kg; IV; Q3W) inhibits tumor growth in multiple PDX solid tumor models, achieving complete responses^[4].