CaMKII (Ca2+/calmodulin-dependent protein kinase II) is an oligomeric protein kinase assembled by 12−14 monomers in a double-layered ring. Structurally, each monomer consists of an N-terminal catalytic domain, a self-regulatory domain and a C-terminal association domain connected via a variable linker.
In the brain, CaMKII consists mainly of a heteromeric complex composed of camKIIα and camKIIβ. CaMKIIα is a brain-relevant kinase. It regulates synaptic signaling through the phosphorylation of ion channels. Besides, it regulates long-term potentiation and synaptic plasticity, and thus modulates brain functions such as learning and memory. Meanwhile, CaMKIIα plays an important role in ischemia and neurodegenerative disorders, e.g., Alzheimer’s and Parkinson’s disease. Together, this makes CaMKIIα an emerging drug target.
Ph-HTBA is a brain-penetrating modulator for CaMKIIα and has a neuroprotective effect.
On the one hand, Ph-HTBA can inhibit HOCPCA binding with a Ki value of 1.4 μM. Ph-HTBA has a high affinity for the CaMKIIα binding site with a Kd value of 757 nM. Meanwhile, Ph-HTBA has a marked hub thermal stabilization effect along with a distinct CaMKIIα Trp403 flip upon binding.
On the other hand, Ph-HTBA reduces Ca2+-stimulated autophosphorylation and substrate phosphorylation, which is potentially contributing to its neuroprotective effect. Furthermore, Ph-HTBA has good cellular permeability and low microsomal clearance and shows brain permeability after systemic administration to mice.
Altogether, Ph-HTBA is a high-affinity, brain-penetrating modulator for CaMKIIα, which can be used for the research of neurodegenerative disorders.