Development of a dual MDM2/XIAP inhibitor with a high therapeutic index for childhood 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.The oncoproteins 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.A recent collaboration at UTHSC and Emory led to the discovery and patenting of the small molecule MX69- 52 as a MDM2/XIAP dual inhibitor. MX69-52 binds to the MDM2 RING domain and disrupts its interaction with XIAP IRES, resulting in simultaneous inhibition of both MDM2 and XIAP, leading to cancer cell apoptosis. MX69- 52 has an MTD ≥200 mg/kg and is effective against leukemia xenograft models at 15 mg/kg, suggesting a large therapeutic index. SEAK Therapeutics licensed this patented scaffold and aims to develop the most potent isomer within the isomeric mixture MX69-52, namely MX69-52d, as a more effective drug for pediatric cancers. SEAK Therapeutics proposes in this Phase I SBIR to characterize and de-risk MX69-52d as a viable clinical candidate and to provide proof of concept for this approach.Aim 1. Generate sufficient amounts of the most potent optical isomer MX69-52d and determine its absolute structure. Milestones: (1) produce 500 mg of MX69-52d (purity ≥ 98%); (2) unambiguously determined the absolute structure of MX69-52d to enable future development of a stereo-specific synthesis.Aim 2. Confirm MDM2/XIAP dual inhibition by MX69-52d and evaluate its potential off-target effects against a panel of physiologically important targets. We will confirm that MX69-52d maintains its mode of action similar to that of its isomeric mixture MX69-52. We will also map its potential off-target effects using Cerep’s Safety47 panel. Milestones: (3) confirmed dual MDM2/XIAP inhibitory abilities of MX69-52d in both biochemical and cellular assays; (4) identified potential interactions at 10 µM on physiologically important targets (e.g., GPCRs, ion channels, transporters) to further de-risk MX69-52d.Aim 3. Determine maximum tolerated dose (MTD) and pharmacokinetic (PK) parameters of MX69-52d, 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 MX69-52d using two mouse models of pediatric cancers. Milestones: (5) the MTD of MX69-52d (≥200 mg/kg) and PK parameters; (6) demonstrated anti-cancer efficacy without acute toxicities at ≤20 mg/kg.Success of this work will set the stage for a Phase II SBIR focusing on the development of MX69-52d or an improved analog through pre-IND studies, with the goal to develop a more effective drug for pediatric cancers.Project NarrativeThe main treatment strategies (radiation therapy or chemotherapy) for pediatric cancer treatments are often associated with severe side effects, and 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 MX69-52d, as a targeted drug with a high therapeutic index for improved treatment outcomes in pediatric cancer patients. Success of this Phase I study will allow SEAK Therapeutics to develop solid foundations for entrance of a SBIR Phase II in further developing MX69-52d 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 such as non-small cell lung cancer, breast cancer and aggressive brain tumors, where overexpression of MDM2 and XIAP are present.