mdm2 in 1

MDM2-IN-1 is a synthetic MDM2-p53 interaction (MDM2) inhibitor and contains the trans (D-)configuration.

MDM2/XIAP-IN-1 (compound 14) is an orally active dual inhibitor of MDM2 and XIAP, displaying anti-cancer activity with an IC50 of 0.3 μM and potential applications in cancer research [1].

p53-MDM2-IN-1 (Example 30), an inhibitor of the p53-MDM2/X protein interaction, exhibits a K i value of 23.35 µM and holds potential for applications in anti-tumor research.

CDK2/MDM2-IN-1 (III-13) is a dual inhibitor targeting both CDK2 and MDM2, exhibiting an IC50 value of 2.60 nM against CDK2, and demonstrating antitumor activity.

BI-0252 is an inhibitor of MDM2-p53 (IC50:4 nM). BI-0252 can induce tumor regressions in all animals of a mouse SJSA-1 xenograft. And it concomitant induction of the tumor protein p53 (TP53) target genes and markers of apoptosis.

ERRα Ligand-Linker Conjugates 1 refers to a chemical compound that consists of a ligand targeting estrogen-related receptor alpha (ERRα), and a PROTAC linker that facilitates the recruitment of E3 ligases MDM2. It finds utility in the synthesis of a range of PROTACs, including one known as PROTAC ERRalpha Degrader-1. With its capability to induce degradation of ERRα, PROTAC ERRalpha Degrader-1 functions as an ERRα degrader[1].

K-Ras ligand-Linker Conjugate 1 is a chemical compound that includes a ligand for K-Ras and a PROTAC linker, facilitating the recruitment of E3 ligases VHL, CRBN, MDM2, and IAP. It can be utilized in the synthesis of PROTAC K-Ras Degrader-1, a highly effective K-Ras degrader that achieves ≥70% degradation efficacy in SW1573 cells [1].

K-Ras ligand-Linker Conjugate 2 is a chemical compound that includes a ligand for K-Ras and a PROTAC linker, capable of recruiting E3 ligases like VHL, CRBN, MDM2, and IAP. It is utilized in synthesizing PROTAC K-Ras Degrader-1, a highly effective PROTAC K-Ras degrader with a degradation efficacy of ≥70% in SW1573 cells[1].

K-Ras ligand-Linker Conjugate 3 (Compound 001371) is a chemical compound comprising a ligand for the K-Ras recruiting moiety and a PROTAC linker, responsible for recruiting E3 ligases (e.g., VHL, CRBN, MDM2, and IAP). This compound is essential for synthesizing PROTAC K-Ras Degrader-1, a potent degrader with a degradation efficacy of ≥70% in SW1573 cells[1].

K-Ras ligand-Linker Conjugate 4 is a chemical compound combining a K-Ras recruiting ligand with a PROTAC linker, responsible for recruiting E3 ligases such as VHL, CRBN, MDM2, and IAP. It has the potential to be used in synthesizing PROTAC K-Ras Degrader-1, which shows a degradation efficacy of ≥70% in SW1573 cells[1].

K-Ras ligand-Linker Conjugate 5 is a chemical compound combining a K-Ras recruiting ligand with a PROTAC linker for E3 ligases, such as VHL, CRBN, MDM2, and IAP. This conjugate is crucial for synthesizing PROTAC K-Ras Degrader-1, displaying a degradation efficacy of ≥70% in SW1573 cells [1].

HL001 is an orally active small molecule inhibitor of cyclophilin A (CypA) and a receptor antagonist of lysophosphatidic acid 1 (LPA1). It induces cell cycle arrest and apoptosis in tumor cells via p53. By downregulating G3BP1, HL001 promotes reactive oxygen species production and DNA damage to stabilize p53. It disrupts the interaction between MDM2 and p53-72R in a CypA-dependent manner. HL001 exhibits antitumor activity and can also be used in research on pulmonary fibrosis.

ASTX295 is a selective mouse double minute 2 (MDM2) antagonist with an IC50 value of less than 1 nM. It specifically inhibits the interaction between MDM2 and p53, reactivating wild-type (WT) TP53, which subsequently induces the expression of related transcriptional targets, leading to cell death and cell cycle arrest. ASTX295 holds potential for research in lymphoid malignancies such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and T-cell lymphoma.

YL-1-9 is an inhibitor that prevents the degradation of p53 by MDM2 through tight binding to the crucial hydrophobic pocket of MDM2. It can induce cell cycle arrest and apoptosis in breast cancer cells [1].

PROTACMAGLdegrader-1 is an orally active PROTAC agent that simultaneously targets both monoacylglycerol lipase (MAGL) and the E3 ubiquitin ligase MDM2. It functions by degrading MAGL and inhibiting the interaction between MDM2 and p53. Additionally, PROTACMAGLdegrader-1 has partial blood-brain barrier (BBB) penetration and can induce apoptosis in glioblastoma stem cells (GSC).

(Rac)-PROTAC PARP/EGFR ligand 1 is a compound that includes ligands for target proteins PARP and EGFR, along with a PROTAC linker that recruits E3 ligases such as VHL, CRBN, MDM2, and IAP. It is utilized in the synthesis of PROTAC DP-C-4, a dual CRBN-based PROTAC designed for the concurrent degradation of EGFR and PARP.

MMRi6 is an inhibitor of the Mdm2-MdmX RING domain, capable of disrupting Mdm2-MdmX RING-RING interactions in vitro. It inhibits MdmX-stimulated Mdm2 autoubiquitination and Mdm2-MdmX-mediated polyubiquitination of p53 without affecting NEDD4-1 autoubiquitination. In wt-p53 Emu-myc lymphoma cells, MMRi6 induces p53 stabilization and accumulation, as well as PARP cleavage. It inhibits the growth of wt-p53 and p53-null Emu-myc lymphoma cells, with IC50 values of approximately 0.5 μM and 3 μM, respectively. MMRi6 is applicable in leukemia/lymphoma research.

K-Rasligand-Linker Conjugate 6 formate includes a target protein K-Ras ligand (K-Ras recruitment motif) and a PROTAC linker, capable of recruiting E3 ligases such as VHL, CRBN, MDM2, and IAP. It is utilized in synthesizing PROTACK-Ras Degrader-1, a potent PROTACK-Ras degrader, achieving a K-Ras degradation rate of ≥70% in SW1573.

AM-6761 is a potent inhibitor of the MDM2-p53 interaction. In the SJSA-1 osteosarcoma xenograft model, AM-6761 shows excellent antitumor activity with an ED50 of 11 mg/kg.

MRT80 is an inhibitor of GSK-3 in vitro. MRT80 de-stabilizes MDM2 and stabilizes p53 protein and E2F-1.

Nutlin-3 is an activator of p53 that functions by inhibiting the interaction of p53 with MDM2, a negative regulator of p53 activity. Caylin-1 is a nutlin-3 analog which contains chlorine substituents at the 3 and 4 positions on two of the phenyl rings rather than a single 4-chloro as seen in nutlin-3. At high concentrations, caylin-1 inhibits the growth of HCT116 cells with an IC50 value of approximately 7 μM, making it about 7-fold less potent than nutlin-3 in the same assay. Interestingly, at concentrations at or below 1 μM, caylin-1 promotes the growth of HCT116 cells approximately 20% compared to untreated cells. The mechanism of the growth promoting properties of caylin-1 have not yet been elucidated.

BTX161 is a Thalidomide analogue. BTX161 is a potent CKIα degrader. In human AML cells, BTX161 mediates the CKIα degradation better than Lenalidomide as well as activates DNA damage response (DDR) and p53, and also stabilizes the p53 antagonist MDM2[1].

NSC405640 is a highly effective compound that inhibits the interaction between MDM2 and p53 proteins. Furthermore, it can restore the structural integrity of p53 molecules affected by mutations. Notably, NSC405640 exhibits selectivity in inhibiting the growth of cell lines that possess the normal, unmutated form of the p53 protein [1].

Milademetan (DS-3032) tosylate hydrate, an orally active and specific MDM2 inhibitor, is utilized in the study of acute myeloid leukemia (AML) and solid tumors. It induces G1 cell cycle arrest, senescence, and apoptosis, showcasing its therapeutic potential [1] [2].