8D6E
Crystal Structure of Human Myt1 Kinase domain Bounded with RP-6306
Summary for 8D6E
| Entry DOI | 10.2210/pdb8d6e/pdb |
| Descriptor | Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, SULFATE ION, (1P)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide, ... (6 entities in total) |
| Functional Keywords | kinase inhibitor complex, signaling protein, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 70858.24 |
| Authors | Pau, V.P.T.,Mao, D.Y.L.,Mader, P.,Orlicky, S.,Sicheri, F. (deposition date: 2022-06-06, release date: 2022-07-27, Last modification date: 2023-10-18) |
| Primary citation | Szychowski, J.,Papp, R.,Dietrich, E.,Liu, B.,Vallee, F.,Leclaire, M.E.,Fourtounis, J.,Martino, G.,Perryman, A.L.,Pau, V.,Yin, S.Y.,Mader, P.,Roulston, A.,Truchon, J.F.,Marshall, C.G.,Diallo, M.,Duffy, N.M.,Stocco, R.,Godbout, C.,Bonneau-Fortin, A.,Kryczka, R.,Bhaskaran, V.,Mao, D.,Orlicky, S.,Beaulieu, P.,Turcotte, P.,Kurinov, I.,Sicheri, F.,Mamane, Y.,Gallant, M.,Black, W.C. Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306. J.Med.Chem., 65:10251-10284, 2022 Cited by PubMed Abstract: PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. inhibits -amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors. PubMed: 35880755DOI: 10.1021/acs.jmedchem.2c00552 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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