- Reata is developing a novel class of C-terminal Hsp90 modulators. Modulation of Hsp90 may result in activation of Hsp70, a molecular chaperone that plays a critical role in the process through which a protein assumes its functional shape and that serves as a central gatekeeper for mitochondrial protein import. Mitochondria rely on Hsp70-dependent protein import mechanisms for almost all of their activity, including the production of ATP1. There are also indications that Hsp70 activation may play a profound role in neuroprotection since nerve cells are high consumers of ATP and rely on Hsp70-dependent protein import for proper mitochondrial function2.
- Our lead compound in this class, RTA 901, has shown favorable activity in a range of preclinical models of neurodegeneration and neuroprotection, including diabetic neuropathy and neural inflammation, as well as positive effects on mitochondrial bioenergetics.
- RTA 901 completed a Phase 1 clinical trial. We encountered no safety or tolerability issues and observed an acceptable pharmacokinetic profile in the trial.
Neuroprotective and Neuroregeneration Potential
Reata’s Hsp90 modulators, including RTA 901, are highly potent and selective C-terminal modulators of Hsp90. Modulation of Hsp90 may result in activation of Hsp70, a molecular chaperone that plays a critical role in the process through which a protein assumes its functional shape and that serves as a central gatekeeper for mitochondrial protein import. Mitochondria rely on Hsp70-dependent protein import mechanisms for almost all of their activity, including the production of ATP1. Recent insights have indicated a potentially profound role of Hsp70 activation in neuroprotection and neuronal regeneration, since nerve cells are particularly high consumers of ATP and rely heavily on Hsp70-dependent protein import for proper mitochondrial function2. The role of Hsp70 in quality control of protein expression is also significant in the context of many neurodegenerative diseases, which involve toxic aggregation of misfolded proteins.
Reata’s lead molecules from this program have demonstrated nonclinical activity in a range of models of neurodegeneration and neuroprotection, including diabetic neuropathy and neural inflammation. These agents have shown significant rescue of nerve function, restoration of thermal and mechanical sensitivity, improvement in nerve conductance velocity, and increases in mitochondrial function of relevant neuronal tissues in rodent disease models5. The effects with RTA 901 are achieved with once-daily oral dosing in these preclinical models6. RTA 901 also has demonstrated acceptable tolerability in early GLP toxicology studies. Reata’s Hsp90 modulators also have shown significant neuroprotective activity in models of Alzheimer’s disease7 and demyelinating motor nerve diseases8.
Clinical Development Program
- Fan et al. Function of cytosolic chaperones in Tom70-mediated mitochondrial import. Protein Pept Lett; 18(2) 122-31.
- Brown. Heat shock proteins and protection of the nervous system. Ann N Y Acad Sci. 2007; 1113:147-58.
- Santoro et al. Heat shock factors and control of the stress response. Biochem Pharmacol. 2000; 59(1):55-63.
- Turturici et al. Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. 2011; 2011: 618127.
- Ma et al. Heat shock protein 70 is necessary to improve mitochondrial bioenergetics and reverse diabetic sensory neuropathy following KU-32 therapy. J Pharmacol Exp Ther. 2014; 348(2):281-92.
- Reata Pharmaceuticals, Inc., internal data.
- Menchen et al. Neuronal protection by a novel C-terminal Hsp90 modulator. KU ScholarWorks Dissertation. 2012.
- Li et al. Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induced demyelination by enhancing the proteasomal clearance of c-Jun. ASN Neuro. 2012; 4(7): e00102.