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Structure-guided optimization of an in vivo active small molecule antitubercular targeting KasA

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI134561-01A1
Agency Tracking Number: R41AI134561
Amount: $224,998.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA17-303
Timeline
Solicitation Year: 2017
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-02-07
Award End Date (Contract End Date): 2019-07-31
Small Business Information
5616 HILLTOP NEEDMORE RD
Fuquay Varina, NC 27526-9278
United States
DUNS: 079704473
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 SEAN EKINS
 (215) 687-1320
 collaborationspharma@gmail.com
Business Contact
 SEAN EKINS
Phone: (215) 687-1320
Email: collaborationspharma@gmail.com
Research Institution
 RBHS-NEW JERSEY MEDICAL SCHOOL
 
185 S ORANGE AVE
NEWARK, NJ 07103-2757
United States

 Nonprofit college or university
Abstract

Project Summary
The continued spread of drug resistant Mycobacterium tuberculosisMtbinfections has rendered tuberculosisTBa global health pandemic and pressed home the urgent need for new drugsCompounds which inhibit
essential components of the Mtb cell wall rapidly cause cell death and are represented clinically by isoniazidIf
any drug combination is likely to reduce treatment duration and prevent the emergence of new antibacterial
resistanceit will be a sterilizing synergistically acting therapyIn this proposalour aim is to develop a new TB
therapy that targets a validated druggable pathway and commences with a validated lead compoundThe longterm goal is a new drug effective against both drug susceptible and drug resistant MtbThe drug lead DGtargets KasAan essential enzyme involved in mycolic acid biosynthesisThe atomic scale interactions between
KasA and DGand multiple analogs of differing chemotype have been established in high resolution X ray
crystal structuresOur work corrects a previous GSK structure and shows that two molecules of DGare
bound in KasADGshows synergy in killing studies with the established drug isoniazidDGisoniazid
combinations lead to rapid sterilization of Mtb cultures and show synergy in a mouse model of acute Mtb
infectionA DGisoniazid combination could shorten TB treatment by accelerating clearance of replicating
bacteria in acute TB diseaseHerewe propose to advance lead optimization of DGOur experienced project
team is comprised of academic and industrial researchers with an established track record of collaboration and
the common goal of devising new antitubercular drug therapiesThe complimentary key skill sets in medicinal
chemistrycheminformaticsstructural biologymicrobiologyand pharmacokinetics pharmacodynamics are all
present and will be leveraged to deliver an optimized lead candidate inhibitor of Mtb KasA with enhanced in vivo
efficacy as compared to the early lead DGThis will prepare us for a Phase II program that would complete
the optimization and set the stage for pre IND toxicology studies Project Narrative
Drug resistant Mycobacterium tuberculosisMtbinfections have rendered tuberculosisTBa global health
pandemic and there is an urgent need for new antitubercular drugsCompounds which inhibit essential
components of the Mtb cell wall rapidly cause cell death and are represented clinically by isoniazidThe drug
lead DGtargets KasAan essential enzyme involved in mycolic acid biosynthesisshows synergy in killing
studies with the front line drug isoniazid and in a mouse model of acute Mtb infectionWe propose to deliver an
optimized lead candidate inhibitor of Mtb KasA with enhanced in vivo efficacy as compared to the early lead
DGin preparation for a Phase II application that would target critical pre clinical studies

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

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