Projects per year
Abstract
A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.
Original language | English |
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Pages (from-to) | 4655-4684 |
Number of pages | 30 |
Journal | Journal of Medicinal Chemistry |
Volume | 63 |
Issue number | 9 |
DOIs | |
Publication status | Published - 14 May 2020 |
Projects
- 4 Finished
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Small molecule therapeutics: from infectious and parasitic diseases to cancers
Baell, J.
1/01/17 → 31/12/21
Project: Research
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Unique and selective small molecules to dissect histone acetyltransferase biology
Baell, J., Thomas, T. & Parker, M.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/15 → 31/12/18
Project: Research
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NHMRC Research Fellowship
Baell, J.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/12 → 31/12/16
Project: Research