Oct 2026· European journal of medicinal chemistry· Vol 321 Pt 2, pp.
119416
· 0 citations· 22 references
Medicine
TL;DR
Mechanistic studies and in vivo experiments demonstrated that intravenous injection of compound B3 could achieve prominent therapeutic efficacy with a high safety profile and indicate that compound B3 is a promising candidate for CRC treatment.
Abstract
In this work, YK-2168 was selected as the lead compound for the development of a series of highly selective CDK9 inhibitors due to its unique 1H-pyrrolo[2,3-b]pyridine scaffold, which acts as an optimal backbone for targeting the kinase hinge region. The optimized compound B3 exhibited potent inhibitory activities at both enzymatic and cellular levels with satisfactory selectivity. Mechanistic studies revealed that compound B3 induces apoptosis in the HCT116 cells by suppressing the phosphorylation of RNA polymerase II at Ser2 site, which further results in the downregulates the expression of apoptosis-related gene and protein (Mcl-1) and triggers the cleavage of caspase 3 and PARP. Pharmacokinetic studies and in vivo experiments demonstrated that intravenous injection of compound B3 could achieve prominent therapeutic efficacy with a high safety profile. In general, these findings indicate that compound B3 is a promising candidate for CRC treatment.
Findings identify AT-11 as an early-stage chromeno[8,7-d]oxazole lead and extend the structure-activity basis for CDK16-directed inhibitor development.
JAK3 is a non-receptor tyrosine kinase that plays an important role in immune signaling pathways. It has long been indicated as a potential target for autoimmune diseases. In this work, a set of 28 novel JAK3 inhibitors were designed around a thieno[3,2-d]pyrimidine core, with aromatic moieties at the 2-position, and a...
Simultaneous inhibition of CDK2 and TRKA presents a promising therapeutic avenue for cancer treatment, capitalizing on the critical roles of CDK2 in cell cycle regulation and TRKA in tumor cell survival and progression. In continuation of our previous work on dual CDK2/TRKA inhibitors, two series of pyrazolo[1,5-a]pyri...
Mohamed H. Attia, Deena S. Lasheen, Nermin Samir et al.· RSC Advances· 0 citations
Mechanistic investigations revealed that 8j induces G1 phase cell cycle arrest and promotes apoptosis, which was corroborated by the observed concentration-dependent downregulation of key cell cycle regulators, including CDK4 and cyclin D1.
Chao Lin, Shao-Feng Sun, Hua-Teng Zhang et al.· Journal of Enzyme Inhibition...· 0 citations
A series of newly synthesized pyrimidine analogues 12a-o was developed as dual CDK2/TrkA inhibitors. Synthesis of the target compounds was achieved via a condensation reaction of methyl trifluoroacetoacetate with thiourea, followed by alkylation with various benzyl chlorides. Subsequent chlorination with POCl3 and fina...
Aya M. Slly, Wafaa A. Ewes, Waleed A. Bayoumi et al.· Bioorganic chemistry (Print)· 0 citations
Compound 6b is identified as a promising lead candidate for further development as a VEGFR-2-targeted anticancer agent and stable backbone behavior, regulated ligand fluctuations, preserved structural compactness, and sustained hydrogen bonding within the 6b-VEGFR-2 complex are identified.
Mohamed El-Naggar, Hend I Abdelaal, Mohamed E Albakri et al.· RSC Advances· 0 citations
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