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

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

---

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

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

---

Targeting Protein Kinase, Membrane-Associated Tyrosine/Threonine 1 (PKMYT1) for Precision Cancer Therapy: From Discovery to Clinical Trial

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(20), С. 17997 - 18016

Опубликована: Окт. 9, 2024

\Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1), an overlooked member of the WEE family responsible for regulating cell cycle transition, has recently emerged as a compelling therapeutic target precision cancer therapy due to its established synthetic lethal relationship with CCNE1 (cyclin E1) amplification. Since first-in-class selective PKMYT1 inhibitor, RP-6306, entered clinical trials in 2021, field experienced renewed interest underscored by growing number inhibitor patents and exploration additional gene alterations, such KRAS/p53 mutations, FBXW7 mutation, PPP2R1A novel partners. This perspective summarizes, first time, structure, function, inhibitors both literature patent applications reported date. Compounds are described focusing on their design optimization process, structural features, biological activity aim promoting further drug discovery efforts targeting potential therapy.

Язык: Английский

---

Discovery of pyrrolopyrimidinone derivatives as potent PKMYT1 inhibitors for the treatment of cancer

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 281, С. 117025 - 117025

Опубликована: Ноя. 5, 2024

Язык: Английский

---

Synthesis of New Pyrazolo[3,4-d]pyrimidine Derivatives: NMR Spectroscopic Characterization, X-Ray, Hirshfeld Surface Analysis, DFT, Molecular Docking, and Antiproliferative Activity Investigations

Molecules, Год журнала: 2024, Номер 29(21), С. 5020 - 5020

Опубликована: Окт. 24, 2024

Four new pyrazolo[3,4-

---

An Efficient And Green Deep Eutectic Solvents Mediated Synthesis Of Substituted Pyrimidine and Pyridine Derivatives as Potential Antibiofilm and Antimicrobial Agents

Опубликована: Янв. 1, 2024

Язык: Английский

---