Discovery of CMNPD31124 as a novel marine-derived PKMYT1 inhibitor for pancreatic ductal adenocarcinoma therapy: computational and biological insights DOI Creative Commons

Chaojie Huang,

Ting Wang, Rui Chen

и другие.

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 9, 2025

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to its late diagnosis, resistance therapy, and a dismal 5-year survival rate only 12%. Overexpression PKMYT1—a key regulator cell cycle—correlates with poor patient outcomes, making it promising therapeutic target. In this study, we identify CMNPD31124, novel marine-derived indole alkaloid, as potent PKMYT1 inhibitor. Molecular docking revealed that CMNPD31124 has superior binding affinity compared reference compound Cpd 4, forming robust interactions critical residues such CYS-190, TYR-121, GLY-122. dynamics simulations further demonstrated stable conformation dynamic adaptability, Chai-1 modeling supporting covalent mechanism at active site. Importantly, in vitro assays showed exhibits an IC 50 18.6 μM MiaPaCa-2 cells 31.7 BXPC3 cells, while concentrations up 80 did not significantly affect normal pancreatic cells. Despite these results, toxicity predictions indicate potential hepatotoxicity neurotoxicity, highlighting need for structural optimization. This work lays solid foundation rational design inhibitors by integrating computational methods insights from marine natural products.

Язык: Английский

Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy DOI

Bo Chen,

Xiaofeng Liu, Tong Mu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

PKMYT1 is a crucial regulator of the cell cycle, particularly involved in G2/M transition through inhibitory phosphorylation CDK1, and promising therapeutic target for cancer therapy. Data mining Roche kinome screen database identified hit characterized by 100% activity at 10 μM concentration, which was further validated with enzymatic assay showing double-digit nanomolar potency. The featured quinolinone central core phenol headgroup. replacement problematic headgroup an indazole moiety induced flip kinase hinge cysteine glycine residues, resulting series derivatives enhanced potency, superior selectivity, no GSH flag. Further structural fine-tuning led to discovery compound 36, novel, selective, potent inhibitor favorable oral pharmacokinetic profiles vivo antitumor efficacy.

Язык: Английский

Процитировано

0
Discovery of CMNPD31124 as a novel marine-derived PKMYT1 inhibitor for pancreatic ductal adenocarcinoma therapy: computational and biological insights DOI Creative Commons

Chaojie Huang,

Ting Wang, Rui Chen

и другие.

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 9, 2025

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to its late diagnosis, resistance therapy, and a dismal 5-year survival rate only 12%. Overexpression PKMYT1—a key regulator cell cycle—correlates with poor patient outcomes, making it promising therapeutic target. In this study, we identify CMNPD31124, novel marine-derived indole alkaloid, as potent PKMYT1 inhibitor. Molecular docking revealed that CMNPD31124 has superior binding affinity compared reference compound Cpd 4, forming robust interactions critical residues such CYS-190, TYR-121, GLY-122. dynamics simulations further demonstrated stable conformation dynamic adaptability, Chai-1 modeling supporting covalent mechanism at active site. Importantly, in vitro assays showed exhibits an IC 50 18.6 μM MiaPaCa-2 cells 31.7 BXPC3 cells, while concentrations up 80 did not significantly affect normal pancreatic cells. Despite these results, toxicity predictions indicate potential hepatotoxicity neurotoxicity, highlighting need for structural optimization. This work lays solid foundation rational design inhibitors by integrating computational methods insights from marine natural products.

Язык: Английский

Процитировано

0