8D6C

Crystal Structure of Human Myt1 Kinase domain Bounded with compound 28

8D6C の概要

• エントリーDOI: 10.2210/pdb8d6c/pdb
• 分子名称: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, 1,2-ETHANEDIOL, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: kinase inhibitor complex, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70381.29

構造登録者

Pau, V.P.T.,Mao, D.Y.L.,Mader, P.,Orlicky, S.,Sicheri, F. (登録日: 2022-06-06, 公開日: 2022-07-27, 最終更新日: 2023-10-18)

主引用文献

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

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: 35880755
DOI: 10.1021/acs.jmedchem.2c00552

実験手法

X-RAY DIFFRACTION (2.2 Å)