LEAD OPTIMIZATION AND TARGET VALIDATION OF NEXT GENERATION PYRIMIDINE-BASED UTROPHIN UPREGULATORS FOR DUCHENNE MUSCULAR DYSTROPHY

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LOOk-UP aims at progressing a recently identified carbahydrazide-pyrimidine utrophin upregulator, namely OX01914, to generate a best-in-classorally administrable small molecule drug for the Duchenne Muscular Dystrophy (DMD), a rare genetic muscle-wasting fatal disease. To this end,Prof Russell and I designed a multidisciplinary and complementary in vitro approach leaning on medicinal chemistry, in vitro High-Throughput (HT)ADME-T profiling, chemoproteomics, and best-in-class molecular biology techniques. By these means I will be able to perform: 1) lead optimizationof OX01914 to identify a safe, stable, and potent lead candidate for preclinical studies; 2) perform chemoproteomic-based target engagementstudies to confirm its modulation of mitochondrial ATP synthase peripheral-stalk subunit b (ATP5F1) protein, previously identified as OX01914potential target; 3) investigate the molecular mechanisms leading to utrophin regulation. To date, DMD is still without a cure. Upregulating utrophin,an endogenous safe dystrophin paralogue, represents one of the most valuable strategies to generate a disease-modifying and accessible therapyfor DMD, applicable to all patients regardless of genetic mutations. On these premises, this MSCA project has the following objectives: WorkPackage 1. To rapidly generate an extended chemical library of OX01914 synthetic analogues using multicomponent reactions. Work Package 2.To identify a safe and metabolically stable lead candidate by in vitro activity assessment and ADME-T profiling of the new generated library. WorkPackage 3. To confirm ATP5F1 target engagement of DMD library using chemoproteomic approaches. Work Package 4. To provide newknowledge on how utrophin is modulated by nearing down biological factors involved, through RNA sequencing and proteome profiling, andinvestigating specific pathways using molecular biology techniques.