Chronic kidney disease (CKD) is a major public health problem in the US with an estimated prevalence of ~2.3 million; 116,000 patients enter hemodialysis or peritoneal dialysis programs yearly. A serious complication in 18-75% 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 3 (STAT3) 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 STAT3 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) 2 domain of STAT3. The most active probe was C188. Using C188 as a scaffold, we performed 2-D similarity screening, 3-D pharmacophore analysis and structure-activity relationship (SAR)-directed medicinal chemistry, which identified C188-9 as a very attractive lead compound. Administration of C188-9 (6.25 mg/Kg/d IP for 14 days) increased muscle weight and grip strength in CKD mice through targeting of STAT3 in muscles and decreasing levels of myostatin protein. More recently, we determined that C188-9 has favorable safety and oral pharmacokinetic properties in mice, rats and dogs. The hypotheses we are interrogating in this proposal are: 1) C188-9 is selective for STAT3 and will not adversely impact normal cell function, including T-cell immunity, and 2) a safe, orally formulated dose of C188-9 can be identified for Phase I studies in patients with CKD. We propose four tightly focused Specific Aims to test these hypotheses.
In Aim 1, we will determine the specificity of C188-9 for binding to STAT3 and its potential for adverse off-target effects.
In Aim 2, we will determine the effect of C188-9 treatment on T cell immunity in mice.
In Aim 3, we will synthesize C188-9 under cGMP-like conditions, characterize it, and optimize its formulation.
In Aim 4, we will perform 14-week GLP toxicology and PK studies to enable an IND application for CKD-induced cachexia. The excellent in vitro and in vivo potency of C188-9 coupled with its high maximum tolerated dose and excellent plasma exposures following oral administration provide strong support for the overarching hypothesis that C188-9 can be used safely and effectively to treat cachexia in CKD patients thereby reducing morbidity and mortality.
Cachexia or muscle wasting diminishes the quality of life and increases morbidity and mortality in 18-75% of the 2.3 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, STAT3, is required for cachexia in CKD and identified a small-molecule STAT3 inhibitor, C188-9, that prevents cachexia when administered to mice with CKD. In this proposal, we will determine C188-9's potential for causing adverse reactions in humans and identify the first safe dose of C188-9 to administer to patients with CKD, which are the next steps in determining if C188-9 can be developed into a treatment for cachexia in CKD patients.
|Jung, Kwang Hwa; Yoo, Wonbeak; Stevenson, Heather L et al. (2017) Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice. Clin Cancer Res 23:5537-5546|