molecules of the month


oral ERK1/2 kinase and phosphorylation inhib

Ph. 1/2 candidate for solid tumors

from SBDD from prior lead

Journal of Medicinal Chemistry

Astex Pharmaceuticals, Cambridge, UK

Structure of ASTX029
1 min read

The Astex ERK1/2 kinase inhibitor, ASTX029, is an oral Ph. I-II candidate for patients with advanced solid tumors. The molecule was derived from fragment screening together with structure-based design. Interestingly, the molecule also blocks the phosphorylation/activation of ERK1/2 in addition to inhibiting its kinase activity, making it potentially more effective. Addressing CYP3A4-mediated metabolism while maintaining favorable physicochemical properties was a key aspect of lead optimization. Though metabolism studies highlighted the oxan ring as a key site of metabolism in lead molecule, the sp3-rich moiety was necessary for potency and physicochemical properties. It was found that replacement of a different region of the molecule improved stability, demonstrating that oxan metabolism is context dependent and serving as another example of a molecule having…

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