Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer treatment that significantly compromises quality of life of cancer patients and survivors. Identification of targets for pharmacological intervention to prevent or reverse CIPN is needed. We investigated exchange protein regulated by cAMP (Epac) as a potential target. Epacs are cAMP-binding proteins known to play a pivotal role in mechanical allodynia induced by nerve injury and inflammation. We demonstrate that global Epac1-knockout (Epac1-/-) male and female mice are protected against paclitaxel-induced mechanical allodynia. In addition, spinal cord astrocyte activation and intraepidermal nerve fiber (IENF) loss are significantly reduced in Epac1-/- mice as compared to wild-type mice. Moreover, Epac1-/- mice do not develop the paclitaxel-induced deficits in mitochondrial bioenergetics in the sciatic nerve that are a hallmark of CIPN. Notably, mice with cell-specific deletion of Epac1 in Nav1.8-positive neurons (N-Epac1-/-) also show reduced paclitaxel-induced mechanical allodynia, astrocyte activation, and IENF loss, indicating that CIPN develops downstream of Epac1 activation in nociceptors. The Epac-inhibitor ESI-09 reversed established paclitaxel-induced mechanical allodynia in wild-type mice even when dosing started 10 days after completion of paclitaxel treatment. In addition, oral administration of ESI-09 suppressed spinal cord astrocyte activation in the spinal cord and protected against IENF loss. Ex vivo, ESI-09 blocked paclitaxel-induced abnormal spontaneous discharges in dorsal root ganglion neurons. Collectively, these findings implicate Epac1 in nociceptors as a novel target for treatment of CIPN. This is clinically relevant because ESI-09 has the potential to reverse a debilitating and long-lasting side effect of cancer treatment.

Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension

“…While Epac activation in different cell types may exert diverse effects, its activation in neurons as well as in cardiomyocytes causes cell damage and leads to disease (Laudette et al, 2019;Okumura et al, 2014;Singhmar et al, 2016;Wang et al, 2013). A recent study further shows that Epac inhibition reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy (Singhmar et al, 2018).…”

Targeting der kleinen GTPasen über ihre regulatorischen Proteine

“…[59] Die Cyanoimin-und Iminketongruppen wurden ebenfalls beide als PA INs-Motive identifiziert. [45a] Die Autoren nahmen an, dass die Dockingergebnisse,d ie In-vitro-und In-vivo-Daten, in denen 26 die Epac1-Knockout-Phänotypen [60] rekapitulieren kann, und die SAR bezüglich der Bedeutung der Chlorsubstituenten des Phenylrings ausreichen, um es als einen Epac-spezifischen Antagonisten und nicht nur als ein PA IN zu bewerten. Weitere strukturelle Modifikationen führten zu Verbindungen mit verbesserter Lçslichkeit, submikromolaren und mikromolaren IC 50 -Werten fürEpac2 bzw.Epac1.…”

Targeting the Small GTPase Superfamily through Their Regulatory Proteins

“…[59] Thec yano-imine and imine-ketone groups have also both been identified as PA INs motifs. [45a] Thea uthors believe the docking results,i nvitro and in vivo data in which 26 can recapitulate Epac1 knockout phenotypes, [60] and SAR regarding the importance of chloro-substituents on the phenyl ring are sufficient to validate it as an Epac-specific antagonist and not simply aP AIN.F urther structural modifications led to compounds with improved solubilities and sub-micromolar and micromolar IC 50 values for Epac2 and Epac1, respectively. [61] TheE SI compounds are examples of competitive cAMP inhibitors;a nu ncompetitive inhibitor of Epac1, CE3F4 (27, Figure 12), was identified by Courilleau et al [62] Using ahighthroughput fluorescent assay,6 40 compounds from the French National Chemical Library were screened for their ability to inhibit Epac1 activity.T he tetrahydroquinoline analogue 27 inhibited the cAMP induced exchange activity of Epac1 with an IC 50 value of 23 mm.…”