# Dual inhibition of MDM2 and XIAP as a therapeutic strategy in cancer

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2024 · $514,428

## Abstract

MDM2 and XIAP are important cell-survival proteins in tumor cells. MDM2 acts as an oncoprotein, promoting
cancer progression mainly through inhibition of the tumor suppressor p53, while the anti-apoptotic protein XIAP
plays a critical role in development of resistance to treatment via inhibition of therapy-induced apoptosis. MDM2
overexpression and upregulated XIAP have been detected in various human cancers but not in normal
cells/tissues, and elevated MDM2 and XIAP expression in tumor cells is associated with disease progression
and poor treatment outcomes.
 Our previous studies elucidated a molecular mechanism by which the MDM2 C-terminal RING domain
interacts with XIAP IRES mRNA resulting in stabilization of MDM2 protein and enhanced translation of XIAP;
this led to concomitantly increased expression of both MDM2 and XIAP, contributing to cancer progression and
drug resistance. We have recently established a fluorescence polarization (FP) assay for use in high-throughput
screening (HTS) of chemical libraries and identified a compound (MX69) that binds to the MDM2 RING domain
and blocks or disrupts its interaction with XIAP IRES mRNA. Blocking this interaction results in simultaneous
inhibition of both MDM2 and XIAP, leading to cancer cell apoptosis and death. The overall goal of this proposal
is to develop a potential novel targeted agent based on the MX69 scaffold against tumors overexpressing MDM2.
As discussed above, these tumors also typically upregulate XIAP in an MDM2-dependent manner, resulting in
enhanced drug resistance.
 Specifically, we will perform computer-aided drug design based on the MX69 structure and iteratively
optimize MDM2 binding and anticancer activity (Aim 1). We will define the molecular and biological
mechanism(s) of action of novel MX69 analogs by solving the X-ray crystal structures of MDM2 in complex with
diverse MX69 analogs to confirm on-target MDM2/XIAP inhibition and to evaluate any potential nonspecific
effects (Aim 2). We will perform preclinical studies to assess compound stability, pharmacokinetic (PK), and
pharmacodynamic (PD) properties of the best MX69 analogs; to evaluate their anticancer activity in vivo using
human cancer-in-mouse models; and to determine any potential toxicity to normal cells/tissues (Aim 3). Upon
completion of this project, we will have determined the feasibility of dual targeting MDM2/XIAP as a novel
therapeutic mechanism, and will have developed promising small molecule inhibitors for further preclinical
evaluations, not only for leukemia and neuroblastoma as studied in this proposal, but also in other cancer types.

## Key facts

- **NIH application ID:** 10871884
- **Project number:** 5R01CA240447-05
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** WEI LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $514,428
- **Award type:** 5
- **Project period:** 2020-07-28 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871884

## Citation

> US National Institutes of Health, RePORTER application 10871884, Dual inhibition of MDM2 and XIAP as a therapeutic strategy in cancer (5R01CA240447-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871884. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*