Daniel K. Nomura, Professor of Chemical Biology and Molecular Therapeutics at UC Berkeley and Director of the Novartis-Berkeley Translational Chemical Biology Institute, shared on LinkedIn:
“Excited to share our latest preprint from the lab, led by Taylor Nuttall, in collaboration with our colleagues at Gilead Sciences!
In this study, we tackled PAX8, a lineage-defining oncogenic transcription factor and major dependency in ovarian cancer that has remained largely inaccessible to direct small-molecule targeting.
By screening >3,000 cysteine-reactive molecules, Taylor discovered KL6-159A, a covalent sulfinyl aziridine that directly and stereoselectively engages C57 of PAX8, destabilizes PAX8, suppresses its transcriptional activity, and leads to its degradation.
We show that KL6-159A selectively targets PAX8 and collapses the downstream PAX8 transcriptional program, with FOXM1 emerging as the most strongly suppressed regulatory network.
More broadly, this work adds PAX8 to a growing collection of traditionally ‘undruggable’ transcription factors that we and others are finding can actually harbor ligandable, reactive amino acid hotspots.
We think systematically exploiting these hidden chemical vulnerabilities could open up a much larger fraction of the transcription factor proteome to direct pharmacological targeting.”
Title: Stereoselective Covalent Inhibitor of the Ovarian Cancer-Driving Transcription Factor PAX8
Authors: Taylor M Nuttall, Aman Modi, Kelvin Li, Emily A Lau, Alicia Zhang, Bhavna Malik, Tezcan Guney, John Eksterowicz, Gregory T Notte, Thomas J Maimone, Daniel K Nomura
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