6PDG
Crystal structure of MYST acetyltransferase domain in complex with inhibitor 83
Summary for 6PDG
| Entry DOI | 10.2210/pdb6pdg/pdb |
| Descriptor | Histone acetyltransferase KAT8, ZINC ION, SODIUM ION, ... (7 entities in total) |
| Functional Keywords | inhibitor, complex, myst, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32712.88 |
| Authors | Hermans, S.J.,Parker, M.W.,Thomas, T.,Baell, J.B. (deposition date: 2019-06-18, release date: 2020-04-01, Last modification date: 2024-10-23) |
| Primary citation | Priebbenow, D.L.,Leaver, D.J.,Nguyen, N.,Cleary, B.,Lagiakos, H.R.,Sanchez, J.,Xue, L.,Huang, F.,Sun, Y.,Mujumdar, P.,Mudududdla, R.,Varghese, S.,Teguh, S.,Charman, S.A.,White, K.L.,Shackleford, D.M.,Katneni, K.,Cuellar, M.,Strasser, J.M.,Dahlin, J.L.,Walters, M.A.,Street, I.P.,Monahan, B.J.,Jarman, K.E.,Jousset Sabroux, H.,Falk, H.,Chung, M.C.,Hermans, S.J.,Downer, N.L.,Parker, M.W.,Voss, A.K.,Thomas, T.,Baell, J.B. Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents. J.Med.Chem., 63:4655-4684, 2020 Cited by PubMed Abstract: A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (), a unique aryl acylsulfonohydrazide with an IC 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 and . These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 () 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 (). This compound is a highly potent KAT6A inhibitor (IC = 6.3 nM; = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats. PubMed: 32118427DOI: 10.1021/acs.jmedchem.9b02071 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.919 Å) |
Structure validation
Download full validation report
