BPN-27332 targets ALOX15 to treat ischemic stroke injury

ALOX15 is increased following stroke in humans and mice

The target, ALOX15 (also known as 12/15-lipoxygenase or12/15-LOX), is a lipid-oxidizing enzyme that is increased in neurons and endothelial cells following a stroke, in both humans and rodents.

ALOX15 contributes to 3 mechanisms of cellular injury

On the cellular level, ALOX15 has central roles in several injury mechanisms that cause cell death in neurons, and detrimental signaling pathways in endothelial cells. Lipid peroxidation by activated ALOX15 causes ferroptosis, and binding to mitochondrial membranes leads to AIF translocation to the nucleus and a form of apoptotic cell death. In addition, ALOX15 generates 12-HETE and 15-HETE, signaling molecules that can weaken the vasculature. Blocking ALOX15 activity can therefore provide multimodal protection against ischemic injury.

Developing BPN-27332 as a new drug for ischemic stroke

With support through the NIH Blueprint Neurotherapeutics (BPN) program and based on a previously identified ALOX15 inhibitor as a starting compound, more than 400 novel compounds were synthesized using medicinal chemistry approaches and assayed for their inhibitory activity against recombinant human ALOX15. Counter-screening against related lipoxygenases and cyclooxygenases led to several compounds showing sub-micromolar IC50 values and high (>100x) selectivity. These were tested in a cellular neuroprotection assay and subjected to extensive ADME profiling prior to testing in a rodent model of ischemic stroke. The lead compound, BPN-27332, reduced infarct size in male and female mice by 33.4% and 37.2%, respectively, and showed long-lasting improvement in a battery of neurological tests. We are currently developing BPN-27332 as candidate drug for ischemic stroke.