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

PROJECT SUMMARYAcute 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 andlt;10 mg/kg.Success of this work will set the stage for a Phase II SBIR focusing on the development of SEAK-114b or an improved analog through pre-IND studies, with the goal to develop a more effective drug for pediatric cancers.Project NarrativeCurrently, radiation therapy and chemotherapy are the main treatment strategies for pediatric cancer patients, but they are often associated with severe side effects; thus there is an unmet medical need to develop more efficacious, targeted drugs. In this SBIR project, SEAK Therapeutics proposes to develop a patented small molecule MDM2/XIAP dual inhibitor, named SEAK-114b, as a targeted drug for improved treatment outcomes in pediatric cancers. Success of this Phase I study will allow SEAK Therapeutics to develop solid foundations for entrance of a SBIR Phase II in further developing SEAK-114b or its new derivatives as a new anticancer drug for future clinical trials, not only in pediatric cancers, but also for other refractory cancer types where overexpression of MDM2 and XIAP are present.