Chronic pain is a condition impacting 1 in 8 Australians with adverse effects that can result in complete debilitation and loss of independence. Current therapeutic interventions are largely ineffective or not suitable for long term use due to side effects including tolerance and addiction (opioids) (1).
Adapter-2 Associated Kinase 1 (AAK1) is a key mediator of clathrin mediated endocytosis (CME), a process cells use to internalise cargo. We and others have shown CME inhibition reduces pain, and that this can be achieved through small-molecule AAK1 inhibition (2). This provides a novel, non-opioid treatment for chronic pain, drawing significant attention from various groups. Multiple compounds are currently progressing through clinical trials, e.g., LX9211/pilavapadin has recieved approval for phase III clinical trials for the treatment of diabetic peripheral neuropathic pain (3).
The majority of AAK1 inhibitors thus far conform to a prescriptive structural motif: a cyclic core functionalised with a heterocycle, most commonly an oxazole or pyridine, and a para disposed alkylated amino-acid region (4). Our approach employed a non-classical bioisosteric replacement of this amino acid region with small heterocycles. Compounds were designed through tandem computational approaches including molecular docking and higher-level computational analysis to investigate specific energetic contributions of binding.
Pilot work in this space has resulted in the identification of a new chemotype of AAK1 inhibitor possessing excellent on-target activity equipotent to best-in-class AAK1 inhibitors (incl. LX9211). This has also resulted in the development of a robust computational methodology that is currently being applied in lead optimisation (manuscript in preparation). We believe that it may also be viable for assessing other ligand-protein complexes to aid in high-throughput lead optimisation.