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)

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. We report here that small molecule inhibitors of the cell division cycle kinase 7 (CDC‐7), namely ERP1.14 a and ERP 1.28a, inhibit TDP‐43 hyperphosphorylation‐associated characteristics in lymphoblasts derived from FTLD‐TDP and ALS patients. Interestingly, these inhibitors reverse both the loss of nuclear localization and the nuclear function of TDP‐43‐inducing CDK6 repression. It is suggested that CDC‐7 inhibitors, mainly the heterocyclic compounds here shown, may be considered as promising drug candidates for the ALS/FTD spectrum.