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 development of SEAK-114b or an improved analog through pre-IND studies, with the goal to develop a more effective drug for pediatric cancers.
Currently, 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.
