MDM-2/p53 Degrader

Seldegamadlin (KT-253) is a cereblon-recruiting PROTAC degrader of MDM2, with a DC₅₀ of 0.4 nM. Seldegamadlin catalyzes the ubiquitination and proteasomal degradation of MDM2, disrupts the MDM2/p53 autoregulatory feedback loop, induces apoptosis, caspase activation and p53 target gene expression, and inhibits the growth of wild-type p53 hematologic tumor cells and solid tumor cells. Seldegamadlin is applicable for the research of acute myeloid leukemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma and wild-type p53 solid tumors.

MD-222 is a potent MDM2 PROTAC degrader. MD-222 recruits the CRBN E3 ubiquitin ligase to target and degrade MDM2, and activates the wild-type p53 pathway in cells. MD-222 is used in relevant research on leukemia and breast cancer.

YX-02-030 is a VHL-dependent MDM2 PROTAC degrader with a K_d of 35 nM. YX-02-030 recruits the VHL E3 ligase to form a ternary complex, leading to ubiquitination and proteasome-mediated degradation of MDM2. YX-02-030 inhibits MDM2-p53 and VHL-HIF1α binding with IC₅₀ values of 63 and 1350 nM. YX-02-030 activates TAp73, upregulates p53 family target genes and induces apoptosis. YX-02-030 demonstrates on-target efficacy in TNBC xenograft-bearing mice, extending survival without normal cell toxicity.

MD-4251 is an orally active MDM2 PROTAC degrader with a DC₅₀ of 0.2 nM in RS4;11 cells. MD-4251 induces cereblon-dependent depletion and degradation of MDM2 protein, elevates p53 protein levels and activates p53. MD-4251 inhibits the proliferation of wild-type p53 acute leukemia cells, induces complete and durable tumor regression in xenograft models, and upregulates the protein levels of DSC1, NBEA and CASP14. MD-4251 can be used in studies related to acute leukemia.

MD-265 is a PROTAC degrader targeting MDM2, which activates p53 in cancer cells carrying wild-type p53. MD-265 induces MDM2 degradation by recruiting the CRL4-CRBN ligase complex via the ubiquitination and proteasomal degradation pathway. MD-265 upregulates p53 target genes, induces apoptosis, reduces Mcl-1 levels, increases caspase-3 cleavage, and inhibits colony formation of wild-type p53 leukemia stem cells. MD-265 can be used in research related to leukemia and acute myeloid leukemia.

WB156 is a dual MDM2 and GSPT1 PROTAC degrader with a DC₅₀ of 23 nM against MDM2. WB156 induces the degradation of MDM2 and GSPT1 via the ubiquitin-proteasome system. WB156 upregulates the levels of p53 and p21, and triggers Apoptosis through the cleavage of PARP and Caspase-3. WB156 can be used in leukemia-related research.

WB214 is an MDM2 and GSPT1 molecular glue degrader with human MDM2 K_i >10 μM. WB214 induces a neo-interaction between MDM2 and the cereblon E3 ligase complex, triggering MDM2 ubiquitination, proteasomal degradation, and bystander p53 degradation, and does not bind MDM2’s p53 binding region. WB214 induces GSPT1 degradation, and exhibits anti-proliferative activity in leukemia cells. WB214 can be used for the research of leukemia.

PROTAC MDM2 Degrader-8 is a PROTAC degrader that induces the degradation of the MDM2 protein by recruiting VHL. PROTAC MDM2 Degrader-8 directly binds to MDM2 with a K_D of 38.2 μM; the proteasome inhibitor MG-132 (HY-13259) reverses this degradation effect, supporting that it induces MDM2 degradation via the ubiquitin-proteasome system. PROTAC MDM2 Degrader-8 also upregulates p21, induces apoptosis and cell cycle arrest, and inhibits the migration of MDA-MB-231 cells. PROTAC MDM2 Degrader-8 can be used in studies related to MDM2-targeted protein degradation and triple-negative breast cancer.