Therapeutic potential of novel Cell Division Cycle Kinase 7 inhibitors on TDP‐43‐related pathogenesis such as Frontotemporal Lobar Degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)

Abstract

TDP‐43 has been identified as the major component of protein aggregates found in affected neurons in FTLD‐TDP and amyotrophic lateral sclerosis (ALS) patients. TDP‐43 is hyperphosphorylated, ubiquitinated, and cleaved in the C‐terminus. CDC‐7 was reported to phosphorylate TDP‐43. There are no effective treatments for either FTLD‐TDP or ALS, being a pressing need for the search of new therapies. We hypothesized that modulating CDC‐7 activity with small molecules that are able to interfere with TDP‐43 phosphorylation could be a good therapeutic strategy for these diseases. Here, we have studied the effects of novel brain penetrant, thiopurine‐based, CDC‐7 inhibitors in TDP‐43 homeostasis in immortalized lymphocytes from FTLD‐TDP patients, carriers of a loss‐of‐function GRN mutation, as well as in cells derived from sporadic ALS patients. We found that selective CDC‐7 inhibitors, ERP1.14a and ERP1.28a, are able to decrease the enhanced TDP‐43 phosphorylation in cells derived from FTLD‐TDP and ALS patients and to prevent cytosolic accumulation of TDP‐43. Moreover, treatment of FTLD‐TDP lymphoblasts with CDC‐7 inhibitors leads to recovering the nuclear function of TDP‐43‐inducing CDK6 repression. We suggest that CDC‐7 inhibitors, mainly the heterocyclic compounds here shown, may be considered as promising drug candidates for the ALS/FTD spectrum.

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

“…The observed control of microgliosis and subsequently, the neuroinflammation, together with the significantly prolonged survival of the animals, supported the evaluation of its efficacy in ALS patients (Trias et al, 2016). Moreover, it has been reported that the pharmacological action of masitinib on mast cells and neutrophils may be involved in preventing motoneuron degeneration, contributing to the potential beneficial effect in ALS (Trias et al, 2018).…”

“…These inhibitors are ATP‐competitive, selective among different kinases and predicted to be permeable to the CNS according to the in vitro parallel artificial membrane permeability assay (PAMPA) assay. Moreover, the best compounds of this purine family were selected for further studies in vitro and showed that they were able to recover TDP‐43 homeostasis (decreasing TDP‐43 phosphorylation and recovering nuclear localization) in lymphoblasts from ALS and frontotemporal lobar degeneration patients (Vaca et al, 2020). Finally, these inhibitors, including ERP2.37 (Figure 1) were tested in different in vivo models, such C. elegans and TDP‐43 transgenic mice, confirming the same behaviour (Martinez‐Gonzalez, Rojas‐Prats et al, 2019).…”

Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis

“…We report, here, our results of the treatment of control and sporadic ALS lymphoblasts with Tideglusib, an in-house designed non-ATP competitive GSK-3β inhibitor, that have shown good safety and tolerability in patients with different neurological diseases [23][24][25][26]34]. We have previously demonstrated the usefulness of lymphoblastoid cell lines derived from patients to study TDP-43 homeostasis [27,30] being a suitable platform for preclinical evaluation of potential drug candidates for TDP-43 proteinopathies such as Frontotemporal Dementia (FTD) or ALS [35]. Furthermore, we have shown that by reducing TDP-43 aberrant phosphorylation, we can restore not only TDP-43 homeostasis but also TDP-43 functionality in FTD lymphoblasts [35].…”

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients

“…Cell division cycle kinase 7 (CDC7) plays a role in the hyperphosphorylation of TDP-43, a central protein in the pathogenesis of ALS [43]. Notably, CDC7 inhibitors have shown promise in ALS animal and cellular models by reducing TDP43 phosphorylation [44,45]. Furthermore, a small molecule inhibitor of CDC7 reduced TDP-43 phosphorylation and prevented neurodegeneration in TDP-43-transgenic animals [43].…”