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Proteasome inhibitor re-sensitizing molecules for treatment of refractory multiple myeloma

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA213488-01
Agency Tracking Number: R41CA213488
Amount: $222,958.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA15-270
Timeline
Solicitation Year: 2015
Award Year: 2016
Award Start Date (Proposal Award Date): 2016-09-22
Award End Date (Contract End Date): 2018-02-28
Small Business Information
4120 WHITING ST
Mount Pleasant, SC 29466-7163
United States
DUNS: 078667525
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 FRANK MARCOUX
 (734) 622-7021
 frank.marcoux@wl.com
Business Contact
 NATHAN DOLLOFF
Phone: (215) 272-5203
Email: dolloffn@gmail.com
Research Institution
N/A
Abstract

Project Summary Abstract
Multiple Myeloma MM is the second most common form of blood cancer and remains an incurable and
deadly disease Proteasome inhibitor PI therapy is a cornerstone in the treatment of MM but resistance to
this class of agent is an emerging challenge in the clinic New therapeutic approaches that specifically target
resistance are needed to maximize responses and ultimately produce cures We have identified a hit stage
drug compound E that selectively kills MM cells over normal cells restores the activity of PIs in resistant
MM cells and cures more that of mice with MM without any signs of toxicity We have designed new
derivatives of E that have optimized pharmaceutical properties The specific goals of the proposed project
are to conclusively demonstrate increased metabolic stability and anti MM activity of optimized E
derivatives and to show superior in vivo activity of optimized derivatives using a mouse model of MM
Compounds will be tested as single agents and in combination with FDA approved PIs These study aims are
based on strong preliminary medicinal chemistry work that identified structure activity relationships SAR of
compound E This information has enabled the strategic design of the derivatives that we will test in the
proposed study The proposed experiments capitalize on industry standard assay systems for measuring
pharmacological properties of new drugs in vitro including metabolic stability in blood plasma and liver
microsomes and assays directly measuring drug metabolism by the catechol O methyltransferase COMT
enzyme In vitro assays for measuring anti MM activity and predicting toxicity include the use of panels of
genetically diverse PI sensitive and resistant MM cells and a variety of normal blood and fibroblast cell types
For evaluating the performance of novel derivatives in vivo we will use an established model of experimentally
induced MM that accurately recapitulates the human MM pathology in NOD SCID IL Rgammanull NSG mice
Through the use of these tools and predictions based on a breadth of preliminary data it is our expectation
that this work will deliver a promising new compound for the treatment of refractory MM Narrative Relevance
Proteasome inhibitors are cornerstone therapies in the treatment of Multiple Myeloma MM However
resistance limits their effectiveness and MM remains incurable today Our project will develop a new class of
drug that targets resistant MM and enhances the activity of proteasome inhibitors to improve the duration and
quality of life for MM patients

* Information listed above is at the time of submission. *

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