Table 2.
MDMX inhibitors and their in vitro and in vivo activities and mechanisms of action.
| Inhibitors | Mechanisms of action | In vitro activity | In vivo activity | References |
|---|---|---|---|---|
| STRATEGY 1: BLOCKING MDMX-p53 BINDING | ||||
| SAH-p53-8 | Binds to p53-binding pocket of MDMX and blocks the p53-MDMX binding | Inhibits viability and induces apoptosis in cancer cell lines with wild-type p53 and MDMX/MDM2 overexpression | Suppresses tumor growth in JEG-3 xenograft mouse model | (92) |
| mSF-SAH | Covalently binds to p53-binding pocket of MDMX and blocks the p53-MDMX binding | Nontoxic to p53 null Saos-2 cells | NR | (93) |
| SJ-172550 | Covalently but reversibly binds to p53-binding pocket of MDMX, blocks the p53-MDMX binding, and activates p53 | Induces apoptosis in retinoblastoma cells with wild-type p53 and MDMX overexpression | NR | (94, 95) |
| Compound B1 | Binds to p53-binding pocket of MDMX and blocks the p53-MDMX binding | NR | NR | (96) |
| CTX1 | Binds to MDMX, blocks the p53-MDMX binding, and activates p53 | Induces cancer cell growth arrest and apoptosis alone or in combination with nutlin-3 | Extends survival of mice bearing AML xenograft tumors alone or in combination with nutlin-3 | (97) |
| K-178 | Inhibits the p53-MDMX binding and activates p53 | Inhibits the viability of cancer cell lines with wild-type p53 and MDMX overexpression | Suppresses tumor growth in an HCT116 xenograft mouse model | (98) |
| ATSP-7041 | Binds to MDM2 and MDMX and blocks the p53-MDM2/MDMX bindings | Induces cell cycle arrest in G1 and G2/M phase and apoptosis in cancer cells with wild-type p53 | Suppresses tumor growth in the SJSA-1 and MCF-7 xenograft mouse models | (99) |
| ALRN-6924 | Binds to MDM2 and MDMX and blocks the p53-MDM2/MDMX bindings | Inhibits cell proliferation and clonogenic capacity and induces cell cycle arrest and apoptosis in AML cells with wild-type p53 | Exerts robust anti-leukemic efficacy in AML xenograft mouse models | (100) |
| Protoporphyrin IX | Blocks the p53-MDM2/MDMX bindings and stabilizes p53 and TAp73 | Inhibits proliferation and induces apoptosis in CLL cells without affecting normal cells | NR | (101) |
| STRATEGY 2: INHIBITING MDMX EXPRESSION | ||||
| XI-006 (NSC207895) | Inhibits MDMX promoter activity | Induces cancer cell growth arrest and apoptosis and enhances the anticancer activity of nutlin-3 | NR | (102, 103) |
| XI-011 (NSC146109) | Inhibits MDMX promoter activity | Induces breast cancer cell apoptosis | NR | (104) |
| Luteolin | Decreases MDMX expression by up-regulating microRNA-34a-5p | Inhibits cancer cell proliferation and induces apoptosis | Suppresses tumor growth in an H460 xenograft mouse model | (105) |
| Tanshinone IIA | Inhibits MDMX mRNA synthesis | Induces cancer cell apoptosis alone or in combination with doxorubicin | NR | (106) |
| 25-OCH3-PPD | Inhibits MDMX expression and MDM2-MDMX interaction and induces MDM2 degradation | Inhibits prostate cancer cell proliferation, migration, and invasion | Suppresses prostate tumorigenesis and metastasis in the TRAMP mouse model | (107) |
| ASO | Decreases expression level of MDMX-FL | Reduces the viability of the melanoma and DLBCL cells | Suppresses tumor growth in PDX models of melanoma and DLBCL | (108) |
| GSK3203591 | Induces alternative splicing of MDMX and activates p53 by inhibiting PRMT5 | Inhibits cancer cell growth and survival | Suppresses tumor growth in lymphoma xenograft mouse models | (109) |
| STRATEGY 3: INDUCING MDMX PROTEIN DEGRADATION | ||||
| FL118 | Enhances MDM2-mediated MDMX ubiquitination and degradation | Inhibits cell growth and induces p53-dependent senescence and p53-independent apoptosis in colorectal cancer cells | NR | (110) |
| Inulanolide A | Binds to the RING domains of MDM2 and MDMX and induces their ubiquitination and degradation | Inhibits cancer cell growth, proliferation, migration, and invasion and induces G2/M phase arrest and apoptosis | Suppresses tumor growth and lung metastasis in the MDA-MB-231 orthotopic mouse model | (111, 112) |
| 17AAG | Induces robust MDMX degradation and activates p53 | Induces cancer cell apoptosis alone or in combination with nutlin-3 | Suppresses tumor growth in a RKO xenograft mouse model alone or in combination with nutlin-3 | (113) |
AML, Acute myeloid leukemia; ASO, Antisense oligonucleotide; DLBCL, Diffuse large B cell lymphoma; CLL, Chronic lymphocytic leukemia; NR, Not reported.