Harnessing the Potential of Hosu-53: A Promising DHODH Inhibitor for Hematological Malignancies

The abstract discusses the development of a new drug, HOSU-53, for treating blood cancers like acute myeloid leukemia (AML) and multiple myeloma (MM). Traditional treatments often lead to relapses, but HOSU-53, a DHODH inhibitor, shows promise with its oral availability and target engagement biomarker. The collaboration between Hendrix College and Ohio State University resulted in the synthesis and testing of several compounds, with HOSU-53 standing out for its subnanomolar activity against human DHODH and favorable pharmacokinetic properties.

HOSU-53 demonstrated superior efficacy in a xenograft model compared to a Bayer clinical candidate, with a daily dosage of 10 mg/kg being both effective and tolerable. Higher doses are also safe for intermittent use, and DHO accumulation is a key biomarker for therapeutic responses and toxicity. The drug also showed synergistic effects when combined with decitabine, CD38 antibodies, and a novel combination with CD47 antibody. Additionally, a combination with the FLT3 inhibitor gilteritinib significantly improved survival in a MOLM-13 FLT3-ITD mutant xenograft model.

The research team has completed a comprehensive preclinical evaluation of HOSU-53 as a monotherapy and in combination with other therapies. They are preparing for IND enabling studies, including GLP toxicity studies planned for late 2022, and have initiated human dose projection models. They aim to file an IND application in 2023 for a phase 1 clinical trial for AML and MM.