755039-53-3

Upstream product

• 755039-52-2 (R)-methyl 2-(cyclopentylamino)butanoate 
• 49845-33-2 2,4-Dichloro-5-nitropyrimidine 
• 120-92-3 cyclopentanone 
• 74645-03-7 (R)-2-Aminobuttersaeure-methylester 

Downstream Products

• 1371620-66-4 (R)-7-(2-benzyl-1H-imidazol-1-yl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine 
• 1371620-67-5 (R)-7-(2-benzyl-1H-imidazol-1-yl)-5-cyclopentyl-4-ethyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine 
• 1021853-34-8 1-tert-butyl 4-[(4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzoyl)amino]piperidine-1-carboxylate 
• 1021853-33-7 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-piperidin-4-ylbenzamide 

Relevant academic research and scientific papers

Design, synthesis and biological evaluation of novel pteridinone derivatives possessing a sulfonyl moiety as potent dual inhibitors of PLK1 and BRD4

The simultaneous inhibition of PLK1 and BRD4 by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Herein, two series of novel pteridinone derivatives possessing a sulfonyl moiety were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against HCT116, PC3 and BT474 cell lines. Among them, the most promising compound B2 showed high antiproliferative effects on the three cell lines with IC50 values of 0.30 μM, 1.82 μM and 1.69 μM, respectively. In the enzymatic assay, B2 was identified as a potent PLK1 and BRD4 dual inhibitor (PLK1 IC50 = 6.3 nM, BRD4 IC50 = 179 nM). Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound B2. The results showed that compound B2 obviously inhibited the proliferation of HCT116 cell lines, induced a great decrease in the mitochondrial membrane potential leading to apoptosis of HCT116 cells and arrested the G2 phase of HCT116 cells.

Compound containing methotrexate structure as well as preparation method and application thereof

The invention discloses a compound of a general formula (I) containing a tetrahydrotrexate structure and a preparation method and application thereof. The invention also discloses a composition containing the methotrexate compound or a pharmaceutically ac

Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer

Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way t

Design, synthesis, and biological evaluation of 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as novel dual-PLK1/BRD4 inhibitors

Protein kinase inhibitors and epigenetic regulatory molecules are two main kinds of anticancer drugs developed in recent years. Both kinds of drugs harbor their own advantages and disadvantages in the treatment of cancer, and the development of small mole

Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity

Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound (R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.

Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors

The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase-bromodomain inhibitor (BRD4-BD1 IC50 = 28 nM, PLK1 IC50 = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC50 = 2579 nM, PLK1 IC50 = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.

Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.

Development of Bifunctional Inhibitors of Polo-Like Kinase 1 with Low-Nanomolar Activities Against the Polo-Box Domain

Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.

BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536

A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a Ki = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.

DIHYDROPTERIDINONE DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF

Dihydroperidinone derivatives, preparation process and pharmaceutical use thereof are disclosed. Specially, new dihydroperidinone derivatives represented by general formula (I), wherein each substituent of the general formula (I) is defined as in the description, their preparation process, pharmaceutical compositions comprising said derivatives and their use as therapeutical agents, especially as Plk kinase inhibitors are disclosed.