molecules of the month

8. The Vertex ELOVL1 inhibitor, compound 27, is a potent (13 nM) CNS-penetrant compound that reduces very long chain fatty acid (VLCFA) levels in the CNS, which are believed to be pathological in the rare disease adrenoleukodystrophy (ALD). The starting point came from an HTS on compounds from an internal collection. The molecule demonstrated activity in patient fibroblasts, lymphocytes, and microglia, as well as PD in mouse models of ALD. Unfortunately, preclinical safety findings in the skin, eye, and CNS including irreversible corneal damage in rat as well as seizures and skin lesions in cyno are significant risks to further development. A comparison of the findings to genetic models and data suggests on-target safety liabilities. The Vertex team generously shares safety…