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Oral Small Molecule STAT Inhibitor to Treat Cachexia in Chronic Kidney Disease

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 4R42DK104494-02
Agency Tracking Number: R42DK104494
Amount: $1,499,268.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: 400
Solicitation Number: PA14-054
Timeline
Solicitation Year: 2014
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-04-01
Award End Date (Contract End Date): 2019-03-31
Small Business Information
7000 FANNIN ST STE 2110, Houston, TX, 77030-3833
DUNS: 832672161
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 DAVID TWEARDY
 (713) 792-6517
 djtweardy@mdanderson.org
Business Contact
 DAVID TWEARDY
Phone: (713) 792-6517
Email: djtweardy@mdanderson.org
Research Institution
 UNIVERSITY OF TX MD ANDERSON CAN CTR
 1515 HOLCOMBE BLVD
Unit 0176
HOUSTON, TX, 77030-4009
 Nonprofit college or university
Abstract
DESCRIPTION provided by applicant Chronic kidney disease CKD is a major public health problem in the US with an estimated prevalence of million patients enter hemodialysis or peritoneal dialysis programs yearly A serious complication in of patients with CKD is cachexia or muscle wasting which decreases quality of life and increases morbidity and mortality Unfortunately there are no agents available in the clinic to treat CKD induced cachexia We determined that expression of myostatin a member of the TGF peptide hormone family and the major negative regulator of muscle mass is increased in the skeletal muscles of patients and mice with CKD Blocking myostatin in CKD mice with a humanized myostatin peptibody prevented CKD induced cachexia raising the possibility of using it to treat cachexia in CKD patients However a similar myostatin targeting strategy was halted in Phase I due to unexplained nose and gum bleeding We discovered that CKD in patients and mice activates signal transducer and activator of transcription STAT within skeletal muscles resulting in increased transcription and expression of C EBP which in turn stimulates myostatin expression These findings support the novel hypothesis that an agent that targets STAT could be used to treat CKD induced cachexia To test this hypothesis we used computer based docking and identified three small molecule probes that targeted the phosphotyrosyl peptide binding pocket within the Src homology SH domain of STAT The most active probe was C Using C as a scaffold we performed D similarity screening D pharmacophore analysis and structure activity relationship SAR directed medicinal chemistry which identified C as a very attractive lead compound Administration of C mg Kg d IP for days increased muscle weight and grip strength in CKD mice through targeting of STAT in muscles and decreasing levels of myostatin protein More recently we determined that C has favorable safety and oral pharmacokinetic properties in mice rats and dogs The hypotheses we are interrogating in this proposal are C is selective for STAT and will not adversely impact normal cell function including T cell immunity and a safe orally formulated dose of C can be identified for Phase I studies in patients with CKD We propose four tightly focused Specific Aims to test these hypotheses In Aim we will determine the specificity of C for binding to STAT and its potential for adverse off target effects In Aim we will determine the effect of C treatment on T cell immunity in mice In Aim we will synthesize C under cGMP like conditions characterize it and optimize its formulation In Aim we will perform week GLP toxicology and PK studies to enable an IND application for CKD induced cachexia The excellent in vitro and in vivo potency of C coupled with its high maximum tolerated dose and excellent plasma exposures following oral administration provide strong support for the overarching hypothesis that C can be used safely and effectively to treat cachexia in CKD patients thereby reducing morbidity and mortality PUBLIC HEALTH RELEVANCE Cachexia or muscle wasting diminishes the quality of life and increases morbidity and mortality in of the million patients in the US with chronic kidney disease CKD yet there are no agents available in the clinic to treat it We determined that activation of a protein within skeletal muscle STAT is required for cachexia in CKD and identified a small molecule STAT inhibitor C that prevents cachexia when administered to mice with CKD In this proposal we will determine C andapos s potential for causing adverse reactions in humans and identify the first safe dose of C to administer to patients with CKD which are the next steps in determining if C can be developed into a treatment for cachexia in CKD patients

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

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