Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy

Endogenous bioluminescent reporters reveal a sustained increase in utrophin gene expression upon EZH2 and ERK1/2 inhibition

“…During ontogeny, utrophin expression at the sarcolemma of embryonic skeletal muscle is progressively replaced by dystrophin 27 , 29 and eventually becomes restricted to neuromuscular and myotendinous junctions 28 , 29 . These differences in the temporal distribution of utrophin have encouraged a detailed dissection of UTRN/Utrn regulatory elements 3 , 55 – 60 and studies to investigate how specialised microRNAs 61 , 62 , artificial transcription factors 63 , chromatin modifying drugs 25 , 64 , 65 and other agents 33 , 57 , 66 , 67 can upregulate utrophin as a surrogate for dystrophin in postnatal life 20 . The idea of repurposing the expression of a gene that is normally restricted to earlier stages in development, to remedy the loss-of-function of a similar gene expressed in adults, is not without precedent.…”

“…Myoblast cell lines were derived from these animals to facilitate the screening of interventions that increase Utrn expression and to probe the underlying mechanisms. Bioluminescence screening platforms for utrophin upregulation have been previously described 25 , 33 , 61 , 66 , however, unlike Utrn R mice and myoblasts, these either lack the full genomic context of Utrn or are likely to disrupt the protein structure. Surprisingly, EZH2 inhibitors were shown to increase Utrn expression in cultured myoblasts and this finding was confirmed by genetic ablation of Ezh2 in wildtype myoblasts.…”

“…New bioluminescence-based models that allow non-invasive monitoring of gene expression in vivo are beginning to transform our understanding of epigenetics and disease processes 41 . In addition, bioluminescence-based cell reporters for Utrn are being successfully applied to screen for small molecule modulators of utrophin 66 . The capacity to longitudinally view the expression of multiple genes in concert 42 , 76 offers new opportunities to assess the timing and co-ordinate responses of gene regulatory circuits to drugs and environmental challenges.…”

Gallic acid-based dendrimers with a thiacalix[4]arene core: synthesis, aggregation and use for stabilization of Pd nanoparticles

“…The first step was the synthesis of a dendrimer core (thiacalix [4]arene) containing two or four terminal ethoxypropargyl moieties. For this aim, compounds 1-3 21 were reacted with o-propargyl ethylene glycol 22 under Mitsunobu reaction conditions to give thiacalix [4]arene derivatives 4-6 with 76-79% yields (Scheme 1).…”

Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

“…New treatment approaches to ameliorate the dystrophic phenotype include (i) pharmacological interventions using drugs that modulate the immune response and inflammation, abnormal ion homeostasis, impaired excitation–contraction coupling, cellular growth patterns, abnormal metabolic pathways, cholesterol metabolism, oxidative stress and cardio-respiratory complications [ 8 , 132 , 155 , 209 , 214 ]; (ii) myoblast transfer therapy [ 15 , 225 , 304 ]; (iii) stem cell therapy [ 24 , 40 , 325 ]; (iv) somatic genome editing using CRISPR/Cas9-mediated exon excision [ 12 , 171 , 218 ]; (v) heat shock protein induction to enhance the natural cellular stress response provided by molecular chaperones [ 108 , 334 ]; (vi) stop codon read-through therapy [ 127 , 264 , 326 ]; (vii) vector transfer therapy [ 121 , 242 , 296 ]; (viii) exon-skipping therapy [ 49 , 131 , 180 ]; (ix) electrical nerve stimulation to induce muscle transitions [ 122 ]; and (x) utrophin substitution therapy [ 193 , 312 , 362 ]. An interesting approach is the repurposing of established pharmacological substances and testing of multi-drug combinations in experimental trials using genetic animal models of Duchenne muscular dystrophy [ 383 ].…”