8BJU

HUMAN WEE1 KINASE IN COMPLEX WITH INHIBITOR 1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-2-yl]-2-(2-methoxy-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one

Summary for 8BJU

• Entry DOI: 10.2210/pdb8bju/pdb
• Descriptor: Wee1-like protein kinase, 2-(2-methoxyphenyl)-6-[[4-(4-methylpiperazin-1-yl)phenyl]amino]-1-[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]pyrazolo[3,4-d]pyrimidin-3-one (3 entities in total)
• Functional Keywords: wee1, kinase, protein-inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32735.29

Authors

Musil, D.,Lan, R. (deposition date: 2022-11-06, release date: 2023-05-31, Last modification date: 2024-02-07)

Primary citation

Guler, S.,DiPoto, M.C.,Crespo, A.,Caldwell, R.,Doerfel, B.,Grossmann, N.,Ho, K.,Huck, B.,Jones, C.C.,Lan, R.,Musil, D.,Potnick, J.,Schilke, H.,Sherer, B.,Simon, S.,Sirrenberg, C.,Zhang, Z.,Liu-Bujalski, L.
Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression.
Acs Med.Chem.Lett., 14:566-576, 2023

PubMed Abstract: Wee1 is a tyrosine kinase that is highly expressed in several cancer types. Wee1 inhibition can lead to suppression of tumor cell proliferation and sensitization of cells to the effects of DNA-damaging agents. AZD1775 is a nonselective Wee1 inhibitor for which myelosuppression has been observed as a dose-limiting toxicity. We have applied structure-based drug design (SBDD) to rapidly generate highly selective Wee1 inhibitors that demonstrate better selectivity than AZD1775 against PLK1, which is known to cause myelosuppression (including thrombocytopenia) when inhibited. While selective Wee1 inhibitors described herein still achieved antitumor efficacy, thrombocytopenia was still observed .

PubMed: 37197456
DOI: 10.1021/acsmedchemlett.2c00481

Experimental method

X-RAY DIFFRACTION (1.53 Å)