Targeting DHODH with BAY 2402234: A Promising Approach to Myeloid Malignancy Treatment

Acute myeloid leukemia (AML) is a highly aggressive cancer with a five-year overall survival rate of about 25%, and treatment options, especially for elderly patients, are quite limited. The standard induction chemotherapy with cytarabine and an anthracycline (7+3) has remained largely unchanged since the 1970s. There is a significant need for new therapeutic approaches.

A recent discovery has identified DHODH as a promising target for overcoming differentiation arrest in AML. DHODH is a key enzyme in the de novo pyrimidine synthesis pathway, converting dihydroorotate to orotate. The novel DHODH inhibitor BAY 2402234 has been characterized both structurally and functionally. It is a selective inhibitor of human DHODH enzymatic activity with low-nanomolar potency.

In vitro studies have shown that BAY 2402234 powerfully inhibits the proliferation of AML cell lines and induces their differentiation within a sub-nanomolar to low-nanomolar range. In vivo, it has demonstrated robust anti-tumor efficacy as a monotherapy in various AML xenograft models, including those derived from patient samples. The target engagement of BAY 2402234 is evidenced by increased levels of tumoral and plasma dihydroorotate following treatment.

Consistent with in vitro findings, BAY 2402234 induces AML differentiation in vivo, as indicated by the upregulation of differentiation cell surface markers in xenograft and patient-derived xenograft (PDX) models after treatment. Additionally, it triggers transcriptomic changes associated with differentiation following a single administration.

The clinical investigation of BAY 2402234 is planned to begin in early 2018. This novel inhibitor represents a potential advancement in the treatment of AML and other myeloid malignancies, offering a new approach to differentiation therapy.