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Inhibitors of Mycobacterial Protein Tyrosine Phosphatase B (mPTPB) for therapy of

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI106123-01
Agency Tracking Number: R41AI106123
Amount: $249,269.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA12-089
Timeline
Solicitation Year: 2013
Award Year: 2013
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
351 W. 10TH ST. SUITE 248
INDIANAPOLIS, IN 46202-4122
United States
DUNS: 963401612
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 FRANCIS BURROWS
 (760) 208-6935
 fburrows@aardenpharma.com
Business Contact
 FRANCIS BURROWS
Phone: (760) 208-6935
Email: fburrows@aardenpharma.com
Research Institution
 INDIANA UNIVERSITY
 
980 Indiana Avenue Lockefield Village, RM 2232
INDIANAPOLIS, IN 46202-2915
United States

 () -
 Nonprofit college or university
Abstract

DESCRIPTION (provided by applicant): Inhibitors of Mycobacterial Protein Tyrosine Phosphatase B (mPTPB) for therapy of tuberculosis Aarden Pharmaceuticals Project Summary/Abstract The need exists for a new, breakthrough therapeutic for tuberculosis (TB). Current treatment regimens with toxic chemotherapeutic drugs are too long, causing poor compliance which results in reduced efficacy and the emergence of drug-resistant strains due to incomplete clearance of the infection, resulting in over 1.7 million deaths annually. The WHO has now made the elimination of TB as one of its global development goals of the millennium. The key unmet needs/wants for TB therapy are to shorten the current 6-9 month treatment duration and maintain effectiveness against multidrugresistant TB. Mycobacterial Protein Tyrosine Phosphatase B (mPTPB) is a member of the protein tyrosine phosphatase family of enzymes. TB bacteria encourage their engulfment by host cells of the innate immune system and then 'hide' from and interfere with host immune responses inside these cells. mPTPB is actively secreted into the cytoplasm of infected macrophages, where it undermines host antibacterial defense mechanisms by blocking the production of inflammatory cytokines and preventing the execution of the infected macrophage's 'Plan B', which is to undergo apoptosis to cause death of the infected cell (and its bacterial passengers) for the good of the organism as a whole. In collaboration with our academic cofounder Zhong-Yin Zhang, Aarden has discoveredand characterized several generations of mPTPB inhibitors of increasing potency and selectivity. The most advanced compounds, the L01-Z series, exhibit low nanomolar potency against mPTPB in biochemical and cellular activity assays and display a high degree of selectivity for mPTPB. The lead compound, L01-Z08, is active in a guinea pig model of TB infection. The primary objective of the current proposal is to complete the characterization and Lead Optimization of LO1-Z08, for the treatment of TB, leading to the nomination of L01-Z08 as a clinical development candidate for TB. The secondary objective is the discovery and initial characterization of one or more families of backup compounds with diverse chemical structures. The Specific Aims of the project are: (i) To determine the precise mechanisms of action of L01-Z08 and related compounds in cellular systems by multiple biochemical and recombinant approaches and characterize the activity of mPTPB inhibitors in TB-infected macrophages in vitro (ii) To complete pharmaceutics analyses of L01-Z08 and related compounds, including in vitro ADME, CEREP screen, genetox/micronucleus assays (iii) To synthesize 50-100g of L01-Z08, complete a standard screen to identify a clinical formulation, determine oral bioavailability and perform preliminary toxicology in the rat (iv) To identify potential backup compounds from pre-existing libraries of PTP inhibitors PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The need exists for a new, breakthrough therapeutic forTB - despite the disease burden and the loss of life caused by TB, no new class of drugs has been approved for the treatment of the disease since the 1970s. Current treatment regimens with toxic chemotherapy-type drugs are a too long, causing patient to stop taking the drugs too early, which leads to the emergence of drug-resistant strains of TB. Over a third of world's population is infected with TB, resulting in over 1.7 million deaths annually, and the WHO has now made the elimination of TB as one of its global development goals of the millennium.

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

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