Protein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chemical genetic approach, we report the discovery and further optimization of a number of potent CK-1δ inhibitors. Moreover, these small heterocyclic molecules are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by reduction of TDP-43 neurotoxicity, and are predicted to cross the blood–brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved.

Computer-aided scaffold hopping to identify a novel series of casein kinase 1 delta (CK1d) inhibitors for amyotrophic lateral sclerosis

“…To carry out the 3D-QSAR analysis, the dataset of 47 casein kinase 1 delta inhibitors as new potential drugs for amyotrophic lateral sclerosis, reported recently by Irene G. Salado and coworkers (Salado et al, 2014), was rationally separated into training set of 31, test set of 10 and evaluation set of 6 compounds, respectively (Table 1a-d). The test set was chosen by hierarchical clustering from original dataset (Stoyanov et al, 2006) which was applied as implemented in SYBYL 7.3 (Tripos).…”

“…The complex was typed with CHARMm force field, hydrogen atoms were added and pH of the protein was adjusted to almost neutral 7.4 using protein preparation module. The catalytic enzyme site (ATP-binding activity of kinesin domain) is the preferred binding site for this class of compounds (Salado et al, 2014). In the ATP-binding pocket of kinesin domain Lys38, Pro66, Met80, Met82, Leu84, Leu85 and Asp149 are the active residues which Lys38 and Asp149 form the core catalytic region of ATP and have direct hydrogen bond interaction with many highly potent kinase inhibitors.…”

“…Recently, a set of 47 CK1d inhibitors as new potential drugs for amyotrophic lateral sclerosis have been synthesized and their binding affinities (IC 50 ) have been determined (Salado et al, 2014). Herein, to design novel casein kinase 1 delta inhibitors for amyotrophic lateral sclerosis, CoMFA (Cramer et al, 1988), CoMSIA (Klebe et al, 1994) and AutoGPA (Asakawa et al, 2012) studies were performed to build predictive 3D-QSAR models which resulted in high quality models.…”

Novel group-based QSAR and combinatorial design of CK-1δ inhibitors as neuroprotective agents

“…Death of the motor neurons of the cortex, spinal cord and brain stem is a characteristic of this disease which eventually leads to death of the patient usually resulting from respiratory failure, mostly within 3–5 years from the appearance of symptoms [1]. The term “Amyotrophic” refers to muscle atrophy and weakness which are characteristic to the lower motor neuron disease while “Lateral Sclerosis” occurs due to hardness to palpitation of the lateral columns of spinal cord observed in autopsy specimens [2].…”

“…ALS can be caused by mutations in many different genes such as SOD1 (superoxide dismutase1), TARDBP (transactive response DNA binding protein), and C9orf72 amongst many others [10]. Recently, pathological TDP-43 (transactive response DNA binding protein 43kDA) protein, encoded by TARDBP, has been identified in sALS, which gives scope for development of therapeutic agents [1]. The protein binds to both DNA and RNA.…”