Lysine specific demethylase 1 (KDM1A) is a flavin adenine dinucleotide dependent amine oxidase that binds to transcription factors (TF) regulating gene expression. KDM1A represses gene expression by two main mechanisms: it demethylates activating H3K4me2/1 marks and acts as a scaffold to additional chromatin regulating factors. Small molecule inhibitors targeting the active site of the protein interfere with the enzymatic and scaffolding function of KDM1A. KDM1A is a promising drug target in multiple indications. This interference of small molecule inhibitors with the interaction of KDM1A and the recruiting factors TFs GFI1 and INSM1 is key to the therapeutic effect in acute myeloid leukemia (AML), and small cell lung cancer (SCLC), respectively. Iadademstat is a highly potent and selective KDM1A inhibitor that has been shown to induce differentiation markers and reduce proliferation in sensitive AML cell lines; and to reduce the expression of neuroendocrine lineage markers and proliferation in SCLC. Currently, iadademstat is being tested in two open label Phase IIa clinical trials: in combination with azacitidine in patients with AML; and in combination with carboplatin/etoposide in patients with biomarker positive SCLC.<br/>The use of KDM1A inhibitors is not limited to oncology. The target is also expressed in the CNS, and the brain penetrant KDM1A inhibitor vafidemstat corrects memory deficit and behavioral alterations in rodent models. SRF, GTF2I, OVOL2, and ZNF217 are among the main KDM1A recruiting transcription factors in the brain. Modulation of KDM1A induces genes required for memory, stimulates the response window of immediate early genes, and reduces a neuroinflammatory signature. Vafidemstat was shown to be safe in a Phase I study in healthy volunteers and is currently being evaluated in several Phase IIa trials in Alzheimer’s disease, in multiple sclerosis and in patients with aggression. Preliminary clinical data indicate that vafidemstat could reduce aggression in BPD, ADHD and ASD.<br/>

KDM1A inhibitors iadademstat and vafidemstat from bench to bedside

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.