Medicinal Chemistry Expertise
July 1, 2013 — Califia Bio Phase 2 SBIR Grant for “ Kinase Inhibitors for Treatment of HIV Induced Synaptodendritic Damage.” Califia Bio has been awarded a $1.17 million NIMH Phase 2 Small Business Innovative Research Grant for the discovery of potential treatments for HIV-Associated Neurocognitive Disorder (HAND).
Previously in collaboration with Dr. Harris Gelbard and Stephen Dewhurst at the University of Rochester Medical Center, we have identified URMC-099, a first generation compound that inhibits MLK3 and blocks up-regulation of MCP-1, TNF-α and other inflammatory mediators in HIV-1 Tat stimulated human macrophages. In vivo brain imaging experiments in mice exposed intracerebrally to HIV-1 Tat have shown that i.p. administration of URMC-099 prevents Tat-induced leukocyte infiltration and microglial activation, and reverses Tat-induced damage to synaptic architecture. Damage to synaptic architecture is the key pathological process of HAND in cognition and memory impairment. URMC-099 is a “selectively non-selective” kinase inhibitor and inhibits a large number of protein kinases . In our Phase 1 SBIR research we sought to identify second generation, much more specific MLK3 inhibitors, that would protect neurons in in vitro models of microglial activation by HIV-Tat.
We have successfully discovered a series of potent and much more selective MLK3 inhibitors, exemplified by CLFB-1134, with excellent in vitro activity in neuron protection assays, excellent blood brain barrier penetration, and in vitro safety profiles for CYP450s, hERG and genotoxicity. In Phase 2 research we will optimize these compounds for activity in mouse brain imaging models of HIV-Tat challenge. Compounds showing best efficacy in animal models will be profiled in in vitro safety and genotoxicity screens and dose ranging toxicity studies for selection as development compounds for late stage preclinical testing. Previous MLK3 inhibitors which advanced to clinical testing for HAND and Parkinson’s disease were broad spectrum kinase inhibitors with poor sustained brain levels. We believe the current series of highly selective inhibitors offers promise of providing safe compounds which achieve high levels of CNS exposure.