Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors.

27 Mar 2025·Journal of Medicinal Chemistry

Discovery and Optimization of Novel Apo-IDO1 Inhibitors by a Pharmacophore-Based Structural Simplification Strategy

Article

Author: Cen, Lifang ; Liu, Beibei ; Xu, Yungen ; Huang, Lei ; He, Mingchao ; Ren, Weijie ; Meng, Liuqiong ; Zou, Yi ; Gu, Hongfeng ; Huang, Jingling ; Wu, Yunze ; Zhu, Qihua

Indoleamine 2,3-dioxygenase-1 (IDO1) plays a crucial role in tumor immune escape. However, the limited clinical efficacy of traditional IDO1 inhibitors has impeded their further development. Recently, apo-IDO1 inhibitors that displace the heme to target IDO1 have been discovered, which exhibits a slow dissociation rate reminiscent of irreversible inhibitors. This characteristic suggests sustained target engagement, offering a pharmacodynamic advantage. Therefore, the development of apo-IDO1 inhibitors emerges as a promising strategy in the field of IDO1-related studies. Here, we present the identification of the thienopyrimidine derivative XW-001 through structure-based virtual screening, followed by an iterative optimization process that led to the development of XW-032. XW-032 exhibited remarkable in vitro inhibitory activity against apo-IDO1 (IC₅₀ = 21 ± 5 nM) through a pharmacophore-guided structural simplification approach. Notably, XW-032 (TGI = 63%) exhibited potent in vivo antitumor efficacy in the CT26 syngeneic mouse model, highlighting the benefits of apo-IDO1 inhibitors for tumor immunotherapy.

01 Jul 2024·Bioorganic Chemistry

Synthesis and in vitro antitumor evaluation of new thieno[2,3-d]pyrimidine derivatives as EGFR and DHFR inhibitors

Article

Author: Ghabbour, Hazem A ; Shehata, Ihsan A ; Fouad, Mahasen M ; El-Ashmawy, Mahmoud B

New thienopyrimidine derivatives 2-16 have been synthesized and their in vitro cytotoxicity was evaluated against five different human cancer cell lines HCT-116, Hela, MDA-MB-231, MCF7 and PC3. Compounds 6e, 7a, 7b, 7d, 10c and 10e displayed the highest antitumor activity against all tested cell lines compared to Doxorubicin. Enzyme inhibition assay revealed that compounds 6e and 10e showed high inhibitory activity against EGFR-TK, with IC₅₀ values of 0.133 and 0.151 µM, compared to Olmutinib (IC₅₀ = 0.028 µM); while the highest DHFR inhibitory activity was shown by compounds 7d and 10e with IC₅₀ values of 0.462 and 0.541 µM, compared to Methotrexate (IC₅₀ = 0.117 µM). Cell cycle analysis following a flow cytometric study using colorectal HCT-116 cancer cell line proved that compound 6e induced cell cycle arrest in G0-G1 phase, while compound 10e arrested the cell cycle at both G0-G1 and S phases. Additionally, both compounds (6e and 10e) were potently able to induce apoptosis in HCT-116 cell line. Docking results of compounds 6e and 10e into the pocket of EGFR active site showed their similar main binding features with Olmutinib, while compounds 7d and 10e showed only moderate fitting into DHFR compared to methotrexate. In silico studies revealed that most of the tested compounds obeyed Lipinski's RO5 and showed positive drug likeness scores.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	United States	University of Toledo	-

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