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Development of a dual MDM2/XIAP inhibitor with a high therapeutic index for childhood cancers

Award Number: R43CA246788
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2020

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Development of a dual MDM2/XIAP inhibitor with a high therapeutic index for childhood cancers - 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. 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	SEAK THERAPEUTICS, LLC	3 N DUNLAP ST STE C303	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	1	3/19/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $55,000 )
2020	2020	SEAK THERAPEUTICS, LLC	20 DUDLEY ST STE 900	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	1	8/12/2020	SUPPLEMENT FOR EXPANSION	$55,000
														Subtotal = $55,000

Issue Date FY: 2019 ( Subtotal = $299,823 )
2019	2019	SEAK THERAPEUTICS, LLC	20 DUDLEY ST STE 900	MEMPHIS	TN	38103	SHELBY	USA	Cancer Treatment Research	000	1	9/12/2019	NEW	$299,823
														Subtotal = $299,823

Grand Total All Awards = $354,823

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Development of a dual MDM2/XIAP inhibitor with a high therapeutic index for childhood cancers

Award Number: R43CA246788

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2020

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