8BJT

Structure of human PLK1 in complex with 2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-2-yl]-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one

Summary for 8BJT

• Entry DOI: 10.2210/pdb8bjt/pdb
• Descriptor: Serine/threonine-protein kinase PLK1, ACETATE ION, 1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(prop-2-en-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, ... (5 entities in total)
• Functional Keywords: plk1, selectivity residues, kinase, polo-like kinase, structure based drug design, atp-binding, nucleotide-binding, phosphorylation, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34448.51

Authors

Musil, D.,Liu-Bujalski, L. (deposition date: 2022-11-06, release date: 2023-04-26, 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 (2.188 Å)