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Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies

SETD2, a lysine N-methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that features a t(4,14) translocation. We recently reported the discovery of a novel small-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.

 

Comments:

That sounds like an exciting development! The discovery of a small-molecule inhibitor for SETD2 could indeed be significant, especially considering its role in various cellular processes and its implication in conditions like multiple myeloma.

The progression from an initial tool compound suitable for preclinical studies to an advanced lead for potential clinical evaluation, culminating in EZM0414, highlights the success of your conformational-design-driven approach in chemical evolution.

The potency, selectivity, oral bioavailability, good pharmacokinetic properties, and robust pharmacodynamic activity of EZM0414 in a mouse xenograft model are crucial milestones. This compound could potentially serve as a valuable candidate for further research and development, particularly in the context of therapeutic interventions targeting SETD2 in diseases like multiple myeloma.

The journey from identification to the creation of such a compound must have involved rigorous research and innovative chemical design. What specific challenges did you encounter during this process, and how did you overcome them?

 

Related Products

Cat.No. Product Name Information
E1179 EZM0414 EZM0414 is a potent, selective, and orally bioavailable inhibitor of Histone-lysine N-methyltransferase SETD2.

Related Targets

SETD