# Feasibility study of developing SEAK-114 for the treatment of pediatric cancers

> **NIH NIH R43** · SEAK THERAPEUTICS, LLC · 2020 · $399,964

## Abstract

PROJECT SUMMARY
 Acute lymphoblastic leukemia (ALL) and neuroblastoma (NB) are the most common cancers in children.
Currently treatment options are often associated with severe side effects. Therefore, there is a strong unmet
medical need to develop targeted-drugs with higher therapeutic indexes for improved treatment outcome.
 Both MDM2 and XIAP are important cell-survival proteins in tumors. Elevated MDM2 and XIAP expression
is associated with disease progression and poor treatment outcomes. They represent very attractive cancer drug
targets. While several MDM2-p53 and XIAP inhibitors exist, none of them made to the market yet.
 Collaborations at SEAK Therapeutics, UTHSC, and Emory led to the discovery and patenting of SEAK-114
as a novel MDM2/XIAP dual inhibitor. SEAK-114 binds to the MDM2 RING domain and disrupts its interaction
with XIAP IRES, resulting in simultaneous inhibition of both MDM2 and XIAP. SEAK-114 has an MTD ≥200
mg/kg in mice and is effective against leukemia xenograft models at 10~20 mg/kg, suggesting a large therapeutic
window. SEAK Therapeutics has licensed this patented scaffold and aims to develop the more potent isomer
within the racemic mixture SEAK-114, namely SEAK-114b, as a more effective drug for pediatric cancers. SEAK
Therapeutics proposes in this Phase I SBIR to characterize and de-risk SEAK-114b as a viable clinical candidate.
 Aim 1. Produce sufficient amounts of SEAK-114b and determine its absolute structure. We will scale
up the synthesis of SEAK-114, separate the two optical isomers with our optimized chiral HPLC method to
produce enough pure isomer SEAK-114b for studies in Aims 2 and 3. We will also determine its absolute
structure with X-ray crystallography. Milestones: (1) produce 500 mg of pure SEAK-114b (≥ 98%); (2) determine
the absolute structure of SEAK-114b for subsequent development of its stereo-specific synthesis.
 Aim 2. Confirm MDM2/XIAP dual inhibition by SEAK-114b and evaluate its potential off-target effects
against a panel of physiologically important targets. We will confirm that SEAK-114b maintains its mode of
action similar to its racemate SEAK-114. We will also map its potential off-target effects and safety profiles in
vitro. Milestones: (3) confirm dual MDM2/XIAP inhibition by SEAK-114b in both biochemical and cellular assays;
(4) identify potential interactions with physiologically important targets to further de-risk SEAK-114b.
 Aim 3. Determine maximum tolerated dose (MTD) and pharmacokinetic (PK) parameters of SEAK-
114b, evaluate its anticancer activities in xenograft models, and assess its potential in vivo toxicity to
normal cells/tissues. We will evaluate the improved efficacy and therapeutic index of SEAK-114b using two
mouse models of pediatric cancers. Milestones: (5) the MTD of SEAK-114b (≥200 mg/kg) and PK parameters;
(6) demonstrate anti-cancer efficacy without acute toxicities at <10 mg/kg.
 Success of this work will set the stage for a Phase II SBIR focusing on the dev...

## Key facts

- **NIH application ID:** 10144288
- **Project number:** 1R43CA257324-01
- **Recipient organization:** SEAK THERAPEUTICS, LLC
- **Principal Investigator:** WEI LI
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,964
- **Award type:** 1
- **Project period:** 2020-09-16 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144288

## Citation

> US National Institutes of Health, RePORTER application 10144288, Feasibility study of developing SEAK-114 for the treatment of pediatric cancers (1R43CA257324-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144288. Licensed CC0.

---

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