Developing a kinase inhibitor drug to treat spinal cord injury

ABSTRACT
Spinal cord injury (SCI) is a devastating condition with life-long consequences that include paralysis. Central
nervous system (CNS) axons typically fail to regenerate, leading to irreversible losses of neuronal connectivity
and associated functions after injury. SCI is now estimated to cost the nation’s healthcare system around $40.5
billion annually (CDC). People living with paralysis are often unable to afford health insurance that adequately
covers the associated complex secondary or chronic conditions, which places tremendous economic burden and
psychological suffering on them and their families. Developing a drug to treat SCI will address major healthcare
and societal needs.
Encouraging axon regeneration in the CNS is challenged by at least two separate mechanisms that suppress
axonal growth: 1) a lack of intrinsic regenerative capacity in adult CNS neurons, and 2) the extrinsic inhibitory
microenvironment confronting damaged axons. Despite decades of research and billions of NIH dollars spent,
there are still no approved drugs for promoting axon regeneration. Moreover, the effectiveness of drugs in
development is likely limited by the fact that each targets only one of the two growth-suppressive mechanisms.
We have discovered the first therapeutic candidate, in the form of a small molecule, which can simultaneously
address both sources of regeneration failure. We accomplished this using a combination of phenotypic
screening, target-based profiling, and machine learning to identify kinase targets within each of the two
mechanisms, extrinsic and intrinsic. We then identified a single small molecule (RO48) that manifests a
polypharmacology profile correlated with unusually robust promotion of axon growth. Remarkably, RO48 showed
high and reproducible efficacy in multiple animal models of SCI. We performed preliminary structure activity
relationship (SAR) studies on RO48 with three main motivations: 1) preliminary investigation of the SAR and hit-
to-lead feasibility, 2) improving the potency of RO48 in cell-based assays, and 3) generation of new composition
of matter IP to permit drug development. We were successful in demonstrating SAR and feasibility, as well as
generating new IP (International Patent Application No. PCT/US18/58411, inventors: Al-Ali et al.). Preliminary in
vitro and in vivo DMPK/Tox studies revealed that our chemistry efforts thus far have already eliminated several
liabilities of RO48. In this project, we aim to finalize the SAR studies and generate four lead candidates for animal
testing. We will then prioritize one lead to advance towards a Phase I clinical trial.

Grant Number: 3UH3NS124630-04S1
NIH Institute/Center: NIH
Principal Investigator: Hassan Al Ali