8ZUD

Crystal Structure of Human Myt1 Kinase domain Bounded with compound 8f

This is a non-PDB format compatible entry.

Summary for 8ZUD

• Entry DOI: 10.2210/pdb8zud/pdb
• Descriptor: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, 2-azanyl-3-(2,6-dimethyl-3-oxidanyl-phenyl)-5-(2-morpholin-4-ylpyridin-4-yl)benzamide (3 entities in total)
• Functional Keywords: protein kinase, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32129.57

Authors

Zhang, Z.M.,Zhou, Z.Q. (deposition date: 2024-06-08, release date: 2024-09-11, Last modification date: 2024-09-25)

Primary citation

Wang, C.,Fang, Y.,Zhou, Z.,Liu, Z.,Feng, F.,Wan, X.,Li, Y.,Liu, S.,Ding, J.,Zhang, Z.M.,Xie, H.,Lu, X.
Structure-Based Drug Design of 2-Amino-[1,1'-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of CCNE1 -Amplified Breast Cancer.
J.Med.Chem., 67:15816-15836, 2024

PubMed Abstract: amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for amplification holds promise for the treatment of -amplified breast cancer. Herein, we discover a series of 2-amino-[1,1'-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design. The representative compound exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the -amplified HCC1569 breast cancer cell line and showed synergistic cytotoxicity in combination with gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction of key binding interactions between the inhibitors and residues Asp251 and Tyr121 of PKMYT1 greatly enhanced the potency and selectivity of the compounds.

PubMed: 39163619
DOI: 10.1021/acs.jmedchem.4c01458

Experimental method

X-RAY DIFFRACTION (1.5051008788 Å)