Jul 2026· Biochimica et biophysica acta. Molecular cell research· Vol 1873, pp.
120193
· 0 citations· 75 references
Medicine
TL;DR
These findings identify novel and selective small molecule inhibitors of FoxM1 that effectively disrupt FoxM1-driven oncogenic programs, highlighting their strong potential to evolve into credible anti-cancer therapeutics.
Abstract
The Forkhead box M1 (FoxM1) transcription factor is a well-established oncogenic driver, with its overexpression closely associated with tumor grade, aggressiveness and adverse clinico-pathological features across multiple cancer types. This has garnered considerable therapeutic interest in FoxM1 as a potential target. However, current FoxM1 inhibition strategies suffer from significant limitations or lack clinical validation. In the present study, we employed a structure based rational drug design approach to screen small molecule inhibitors targeting the FoxM1-DNA binding domain (FoxM1-DBD) using the NCI compound library. Selected lead compounds exhibited potent suppression of FoxM1and its targets in CaSki cervical cancer cells, outperforming conventional FoxM1 inhibitors. Electrophoretic Mobility Shift Assay (EMSA) and tryptophan specific fluorescence analyses confirmed direct and specific interaction of the compounds with FoxM1, resulting in effective disruption of FoxM1-DNA binding. Functional characterization revealed that these inhibitors robustly induced apoptosis as evidenced by enhanced PARP and caspase-7 cleavage. Furthermore, the lead compounds demonstrated activity across multiple cancer cell types and markedly attenuated key malignant traits of cancer cells, including proliferation, anchorage-independent growth, migration and invasion. Importantly, FoxM1 knockdown significantly diminished the tumor suppressive effects of the lead compounds thereby affirming target specificity. Collectively, our findings identify novel and selective small molecule inhibitors of FoxM1 that effectively disrupt FoxM1-driven oncogenic programs, highlighting their strong potential to evolve into credible anti-cancer therapeutics.
PE-1 demonstrates dual-target inhibitory activity against the PD-1/PD-L1 immune checkpoint and EZH2, underscoring its potential as a lead compound for the development of next-generation bifunctional anticancer agents.
B. Guan, Binbin Cheng, Hongqiao Li· Frontiers in Immunology· 0 citations
Triple-negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype characterized by a paucity of effective therapeutic options. Consequently, the development of targeted therapies constitutes a promising strategy for TNBC treatment. It has been demonstrated that combining CDK12 and PARP1 inhibitors can trigger synthetic lethality in TNBC cells. In the present study, employing a pharmacophore fusion strategy, we designed and synthesized a series of dual-target inhibitors against CDK12 and PARP1. Among them, compound 20b exerted potent inhibition activity against both CDK12 and PARP1 at nanomolar concentrations. It exhibited markedly superior antiproliferative effects compared with single-target inhibitors and effectively reduced pSer2-CTD (Ser2 phosphorylation) and PAR levels in TNBC cells. Furthermore, compound 20b produced robust colony formation inhibitory effects in TNBC cell lines, accompanied by cell cycle arrest and apoptosis induction. The dual-target CDK12/PARP1 inhibitor 20b developed herein represents a novel lead molecule for TNBC drug development.
Z. Zhong, Miao Sun, Zhiwen Luo et al.· European journal of medicina...· 0 citations
Beyond enabling the discovery of several new potent and selective small molecules, these studies have allowed us to elucidate key parameters for potency, selectivity, and metabolic stability that should aid future efforts in RBP drug discovery.
G. M. Scherer, Jacob P. Sorrentino, A. K. Jaiswal et al.· Journal of Medicinal Chemist...· 0 citations
Signal transducer and activator of transcription 3 (STAT3) is a critical oncogenic driver hyperactivated in approximately 70% of human cancers, especially colorectal cancer (CRC), making it an attractive therapeutic target. Currently, the discovery of STAT3 inhibitors is primarily focused on the SH2 domain, however, there are still problems such as insufficient inhibitory activity and poor clinical efficacy. Targeting the DNA-binding domain (DBD) is a direct and effective strategy for inhibiting STAT3 function; but due to the lack of suitable targeting sites and design methods, reported compounds and their mechanisms of action are limited. Here, we identified a germacrane-type sesquiterpene lactone, SCP-7, from a natural product library through multi-dimensions progressive screening. SCP-7 exhibited potent binding affinity to the STAT3-DBD, with a Kd of 795 nM. Mechanistically, SCP-7 covalently modifies Cys328 and Cys367 of STAT3, as confirmed by mass spectrometry and mutational analysis, with Cys328 serving as the primary binding site and effectively inhibit the DNA-binding activity of STAT3. In CRC cells (HCT116 and HT29), SCP-7 effectively reduced p-STAT3 and c-Myc levels, and inhibited proliferation, migration, and colony formation. Moreover, SCP-7 induced G2/M cell cycle arrest, triggered mitochondrial dysfunction, elevated reactive oxygen species levels, and promoted apoptosis via modulation of BAX, Bcl-2, Mcl-1 and survivin. In a mouse xenograft model, SCP-7 significantly suppressed tumor growth, exhibiting activity comparable to that of oxaliplatin but with a markedly improved safety profile. Collectively, our findings identify SCP-7 as a novel covalent inhibitor targeting the STAT3-DBD with potent anti-CRC activity in vitro and in vivo, providing a promising lead compound for STAT3-targeted cancer therapy.
Yuan-Qing Li, Guxue Zhang, Yuhang Wang et al.· Bioorganic chemistry (Print)· 0 citations
CS18 is established as a chemically distinct TopBP1 inhibitor with translational potential to overcome therapeutic resistance and advance precision oncology.
Fang-Tsyr Lin, Shwu-Jiuan Lin, Kang Liu et al.· Science Advances· 0 citations
