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Identifying Small Molecule Inhibitors of HdmX using Cell-based Screening

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
93550
Program Year/Program:
2009 / SBIR
Agency Tracking Number:
CA139791
Solicitation Year:
N/A
Solicitation Topic Code:
N/A
Solicitation Number:
N/A
Small Business Information
CLEVELAND LEUKEMIA THERAPEUTICS, LLC
11000 CEDAR AVE CLEVELAND, OH 44106-3069
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2009
Title: Identifying Small Molecule Inhibitors of HdmX using Cell-based Screening
Agency: HHS
Contract: 1R43CA139791-01
Award Amount: $188,748.00
 

Abstract:

DESCRIPTION (provided by applicant): Loss of the p53 signaling pathway, either by mutation or loss of upstream or downstream signaling components, occurs in the vast majority of human cancers. In normal cells, Hdm2 and HdmX coordinately regulate the stabil ity and function of p53. However, each protein is overexpressed in subsets of many different types of human malignancy, leading to inactivation of wild-type p53 function. HdmX overexpression was recently reported to be as high as 20% in breast, colon and l ung cancers. Treatment options for tumors harboring wild-type p53 would be greatly expanded if the recent discoveries of low molecular weight compounds capable of disrupting the p53-Hdm2 interaction to induce p53-dependent toxicity continue to show positiv e results. Preliminary comparison of one small molecule's specificity has shown that HdmX and Hdm2 can be differentially affected, thereby establishing each protein as an independent target for therapy. The goal of this proposal is to develop a new class o f small molecules effective against tumor cells retaining wild-type p53 that is transcriptionally repressed due to HdmX overexpression. A cell-based system is proposed that will combine HdmX overexpression with an integrated p53-responsive promoter driving 2- galactosidase expression, an easily measurable and quantifiable specific marker. A screen for compounds that induce p53-dependent transcription will be performed. Candidate compounds that pass through the primary screen will be classified according to their relative strengths and characterized to define the mechanism of p53 activation and the dependence upon HdmX and/or Hdm2 status for efficacy. A limited set of compounds capable of inhibiting HdmX-mediated p53 inactivation will form the basis of a Phas e II program aimed at hit-to-lead optimization and the development of prototype therapeutic drugs. PUBLIC HEALTH RELEVANCE: Cancer cells have acquired genetic alterations that disrupt cellular checkpoints established to limit normal proliferation. In many cancers, these checkpoints are simply suppressed rather than absent, leaving the option to reengage and enforce the hidden limits to proliferation as cancer therapy. We propose to identify compounds that can prevent tumors with a common but specific geneti c alteration, namely HdmX protein overexpression, from continuing their aberrant growth.

Principal Investigator:

Mukesh K. Agarwal
AGARWAMUKESH@YAHOO.COM

Business Contact:

David Wald
Small Business Information at Submission:

CLEVELAND LEUKEMIA THERAPEUTICS, LLC
CLEVELAND LEUKEMIA THERAPEUTICS, LLC 11000 CEDAR AVE, STE 146B CLEVELAND, OH 44106

EIN/Tax ID: 126292798
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No