JBI-802: the first orally available LSD1/HDAC6 dual inhibitor to enter clinical trials.

Introduction: Lysine-specific demethylase 1 (LSD1) and histone deacetylase 6 (HDAC6) are key epigenetic regulators involved in histone demethylation and deacetylation processes that impact chromatin structure and gene expression. JBI-802 marks a major advancement as the first novel, orally available LSD1/HDAC6 dual inhibitor currently in clinical trials.

Areas covered: This review provides a comprehensive overview of the discovery and development of JBI-802, detailing its structure-activity relationship (SARs), chemical synthesis, biological activity, and clinical progress. Other dual LSD1/HDAC6 inhibitors and the challenges are briefly discussed, underscoring the therapeutic potential of dual inhibition in disease treatment. The literature search is performed using SciFinder, Google patent, ClinicalTrials databases, and PubMed.

Expert opinion: The dual LSD1/HDAC6 inhibitor JBI-802 demonstrates robust anti-proliferative activity, significant antitumor effects in multiple hematologic malignancies, and superior efficacy in combination with checkpoint inhibitors in the CT-26 syngeneic mouse model. JBI-802 is currently undergoing phase I/II clinical trials in patients with advanced solid tumors, myeloproliferative neoplasms (MPN), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with thrombocytosis. However, the potential on-target toxicity, off-target interactions and selectivity concerns deservee more attention.