A series of 1,3,5-triazine derivatives bearing N-phenylcyclopropane-1,1-dicarboxamide scaffold were designed, synthesized and evaluated as novel PI3Kα inhibitors. The evaluation of PI3Kα inhibitory activity indicated that some compounds exhibited promising activity...

Twenty-seven novel 1,3,5-triazine derivatives containing benzo[d]imidazole scaffold were designed, synthesized, and evaluated for anti-tumor activity as PI3Kα inhibitors. Assessment of PI3Kα inhibitory effects revealed that some compounds were highly potent in vitro, with seventeen compounds (LNP1, LNP2, LNP4, LNP7-LNP10, LNP12-LNP18, LNP20, LNP23, and LNP24) showing IC50 values less than 100 nM. Notably, LNP23 and LNP24 showed remarkable potency against PI3Kα with IC50 values of 5.15 nM and 8.88 nM, respectively, and thus they were more potent than positive control drug ZSTK474 (PI3Kα, IC50 = 9.89 nM). Compared with ZSTK474, LNP23 and LNP24 also exhibited increased selectivity for PI3Kα over other class I PI3K isoforms. Evaluation of some compounds on MDA-MB-231, MCF-7, and H1975 cell lines revealed that most of them possessed moderate to outstanding antiproliferative activities. LNP23 demonstrated marked inhibitory activity on cell proliferation, with IC50 values of 6.85 μM (MDA-MB-231), 1.29 μM (MCF-7), and 2.13 μM (H1975). Antitumor mechanism of action of compound LNP23 on MCF-7 cells was investigated, including protein expression of p-PI3K and p-AKT by Western blot assay, AO/EB staining assay, hoechst33342 assay, cell apoptosis assays by flow cytometry, cell cycle analysis by flow cytometry, clone formation assay and transwell migration assay. Additionally, the preliminary SARs of these compounds were also discussed.

Based on the scaffold of brigatinib, we designed and synthesized a series of novel EGFR tyrosine kinase inhibitors, followed by the evaluation of their activity against the L858R/T790 M/C797S mutant EGFR kinase. Compound 8c showed significantly higher inhibitory activity (IC50 = 0.48 nM) than brigatinib (IC50 = 3.41 nM), and preferred to inhibit the L858R/T790 M/C797S mutant EGFR kinase rather than other subtypes and ALK. In the proliferation inhibition assays, compound 8c also exhibited significantly greater potency (IC50 = 0.249 μM) and selectivity against BaF3-EGFR(L858R/T790 M/C797S) cell line compared to brigatinib (IC50 = 0.751 μM). Furthermore, cell cycle arrest assay, apoptosis induction assays, Western blot assay, colony formation inhibition assay, cell migration inhibition assays, tube formation assay, and docking analysis were carried out to study the action mechanism of compound 8c. All these results indicated that compound 8c has the potential for further evaluation of in vivo efficacy and druggability.

In this study, we synthesized thirty novel 4-phenoxyquinoline derivatives possessing 2-oxo-1,2-dihydropyridine-3-carboxamide and 6-oxo-1,6-dihydropyridine-3-carboxamide moieties as c-Met kinase inhibitors. The in vitro screening for c-Met inhibitory activity demonstrated that several compounds showed excellent inhibition of c-Met kinase, and IC50 values of seven compounds (YH13, YH14, YH18, YH19, YH22, YH23, YH24) were less than 100 nM. Compound YH14 (c-Met: IC50 = 0.043 μM) showed promising antiproliferative against MKN-45 (IC50 = 0.85 μM), AGS (IC50 = 1.01 μM) and MCF-7 (IC50 = 0.71 μM) cancer cell lines. Meanwhile, the preliminary structure-activity relationships (SARs) studies showed that 6-oxo-1,6-dihydropyridine-3-carboxamide was more preferred as linker part, and morpholinopropoxy group on the 7-position of quinoline ring could improve the antitumor activities. Furthermore, Western blot assay of c-Met and its downstream signaling (PI3K, AKT and ERK), apoptosis induction assays (AO/EB staining and Hoechst33342 staining), Western blot assay of apoptosis-related proteins (Bcl-2 and Bax), cell cycle arrest assay, cell migration inhibition assays, and docking analysis were performed to study the action mechanism of compound YH14.

Thirteen novel 4-phenoxyquinoline derivatives bearing semicarbazone moiety were successfully designed and synthesized based on the structural characteristics of 4-phenoxyquinoline small molecule type II c-Met kinase inhibitors. The in vitro inhibitory activities of all the target compounds against c-Met kinase were evaluated using mobility shift assay. The in vitro antiproliferative activities of the target compounds against A549, PC-3, AGS and MKN45 cells were evaluated using MTT-based assay. Most of the target compounds showed excellent inhibitory activities against c-Met kinase and all the tested cancer cell lines. Among them, compounds 6f(c-Met: IC50=14.50 nmol/L) and 6k(c-Met: IC50=15.68 nmol/L) exhibited excellent inhibition activity of against c-Met kinase. The IC50 values of 6f for A549, PC-3, AGS and MKN-45 cells were 0.93, 7.81, 12.88, and 2.58 mu mol/L, respectively. The IC50 values of 6k for A549, PC-3, AGS and MKN45 cells were 0.67, 6.60, 3.04, and 0.88 mu mol/L, respectively. Further studies on the anti-tumor mechanism indicated that compound 6k induced MKN45 and A549 cells apoptosis, and inhibited the migration ability of MKN45 and A549 cells.

A series of 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives were designed, synthesized and evaluated for their in vitro inhibitory activities against PI3Kα and antiproliferative activities against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cancer cell lines. Inhibitory activities against PI3Kα evaluation indicated that some compounds showed excellent PI3Kα activity in vitro, and IC50 values of eight compounds (17c, 17e, 17f, 17h, 17l, 17m, 17o, 17p) were less than 100 nM. The most promising compound 17f (PI3Kα: IC50 = 0.039 μM) showed remarkable antiproliferative against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cell lines with IC50 values of 3.48 μM, 1.06 μM, 2.21 μM and 0.93 μM, respectively. Furthermore, 17f effectively reduced p-PI3K protein expression and inhibited the activation of downstream signaling AKT and mTOR proteins in MDA-MB-453 cells. In addition, 17f induced cell apoptosis by down-regulating the expression levels of anti-apoptotic proteins Bcl-XL and Bcl-2 and up-regulating the expression of anti-apoptotic protein BAX, and in MDA-MB-453 cells. All these results indicated the potential of compound 17f to develop as potent anticancer agent.

Cancer remains a paramount threat to global health and constitutes a critical frontier in contemporary drug discovery. The pyrazolo[3,4-d]pyrimidine scaffold represents a unique chemical architecture that merges purine and pyrimidine pharmacophores, enabling profound exploration and clinical translation across anti-cancer therapeutic domains. The development of dual-target inhibitors represented a compelling strategy. This combinatorial approach not only amplified pharmacological efficacy through synergistic pathway suppression but also reduced the likelihood of resistance development by disrupting redundant survival networks. This review focused on the emerging paradigm of pyrazolo[3,4-d]pyrimidine-based dual-target inhibitors in oncology. Specifically, we systematically analyzed seven distinct dual-inhibition paradigms: AK/CDK1, HDAC/Topo II, CDK2/GSK-3β, Src/Bcr-Abl, BRAF V600E/VEGFR2, EGFR/PDE5, and EGFR T790M/HER2. Comprehensive insights were provided into the rational design principles, the structure–activity relationships (SARs), and molecular mechanisms underlying these innovative therapeutics. Furthermore, we proposed forward-looking strategies for design, ADME profiling, and toxicity mitigation to guide the translational development of pyrazolo[3,4-d]pyrimidine derivatives in cancer therapy.

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), plays a central role in the post-translational methylation of histone H3 lysine 27 (H3K27me3), thereby regulating gene silencing. Extensive studies have demonstrated that EZH2 is frequently overexpressed in a broad range of malignancies, where it promotes tumorigenesis and progression. Elevated EZH2 expression is strongly associated with increased tumor cell proliferation, invasion, metastasis, therapeutic resistance, higher tumor grade, and poor clinical outcomes. Currently, two EZH2 inhibitors have received regulatory approval for the treatment of cancers such as lymphoma, and both have shown clinical benefit in patients with relapsed or refractory disease. In this review, we provided a systematic analysis of recent advances in EZH2 inhibitor development, with a particular emphasis on classification based on core structural scaffolds. We highlighted the structure–activity relationships (SARs), pharmacological profiles, and the respective advantages and limitations of representative compounds in preclinical development. These insights were intended to offer the design of next-generation EZH2 inhibitors with improved selectivity, safety, and translational potential for targeted cancer therapy.

A series of EGFR inhibitors were designed and synthesized based on the scaffold of osimertinib, the inhibitory activities against the L858R/T790M/C797S mutant EGFR kinase of which were subsequently evaluated. Compounds with the imine fragments showed the highest kinase inhibitory activity and were proved to be reversible inhibitors, which were represented by the compound DD-8 (IC50 = 0.87 nM). Kinase selectivity assay showed the compounds with imine fragments were preferred to inhibit the triple-mutant EGFR kinases rather than other subtypes. In the proliferation inhibition assay against the BaF3-EGFR(L858R/T790M/C797S) cell line, compound DD-8 also showed strong inhibitory activity (IC50 = 1.11 μM), and the inhibition rate of which reached 98.8 % at the concentration of 2 μM. To further elucidate the antitumor mechanism of the compound DD-8, a comprehensive series of experiments were conducted, including apoptosis induction assay, cell cycle arrest assay, western blot assay, cell migration inhibition assay, liver microsomal stability experiment, and molecular docking analysis.

Mantle cell lymphoma (MCL) is a heterogenous disease that is one of the most challenging blood cancers due to its poor prognosis, high risk of relapse and drug resistance. Recent researches have brought significant changes in MCL patients outcomes and new clinical. Bruton's Tyrosine Kinase (BTK), a key kinase in the B-cell antigen receptor (BCR) signaling pathway, is a clinical research hot spot and plays a major role in the survival and spread of malignant B cells. The first generation of BTK inhibitors, led by ibrutinib, have shown promising results in targeted treatment. Meanwhile, several inhibitors have entered clinical studies and demonstrated outstanding therapeutic activity in clinical trials for MCL, indicating a good prospect for development. Despite these encouraging findings, the duration of response is limited, and resistance to BTK inhibitors develops in a portion of individuals. This review summarizes the pathogenesis of MCL and targeted BTK inhibitors and provides an overview of the mutations that can lead to resistance to BTK inhibitors. The purpose of this article is to review the literature describing these selective therapies and provides perspectives for their further development.

The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.

INTRODUCTION:Gastrointestinal stromal tumour (GIST) is a common gastrointestinal sarcoma located in the stromal cells of the digestive tract, and molecular studies have revealed the pathogenesis of mutations in KIT and PDGFRA genes. Since imatinib opened the era of targeted therapy for GIST, tyrosine kinase inhibitors (TKIs) that can treat GIST have been developed successively. However, the lack of new drugs with satisfactory therapeutic standards has made addressing resistance a significant challenge for TKIs in the face of the resistance to first-line and second-line drugs. Therefore, we need to find as many drugs and new treatments that block mutated genes as possible.METHODS:We conducted a comprehensive collection of literature using databases, integrated and analysed the selected literature based on keywords and the comprehensive nature of the articles, and finally wrote articles based on the content of the studies.RESULTS:In this article, we first briefly explained the relationship between GIST and KIT/ PDGFRα and then introduced the related drug treatment. The research progress of TKIs was analyzed according to the resistance of the drugs.CONCLUSION:This article describes the research progress of some TKIs and briefly introduces the currently approved TKIs and some drugs under investigation that may have better therapeutic effects, hoping to provide clues to the research of new drugs.

Pyrazolo[1,5-a]pyrimidines are fused heterocycles that have spawned many biologically active antitumor drugs and are important privileged structures for drug development. Pyrazolo[1,5-a]pyrimidine derivatives have played an important role in the development of antitumor agents due to their structural diversity and good kinase inhibitory activity. In addition to their applications in traditional drug targets such as B-Raf, KDR, Lck, and Src kinase, some small molecule drugs with excellent activity against other kinases (Aurora, Trk, PI3K-γ, FLT-3, C-Met kinases, STING, TRPC) have emerged in recent years. Therefore, based on these antitumor drug targets, small molecule inhibitors containing pyrazolo[1,5-a]pyrimidine scaffold and their structure-activity relationships are summarized and discussed to provide more reference value for the application of this particular structure in antitumor drugs.

Trk gene fusions are an important driver in the development of cancers, including secretory breast cancer and infantile congenital sarcoma. Since the first-generation of small molecule Trk inhibitors (Larotrectinib and Entrectinib) came to market, research on small molecule TRK inhibitors, especially second-generation inhibitors that break through the resistance problem, has developed rapidly. Therefore, this article focuses on the research progress of first-generation drugs and second-generation drugs that break through drug resistance.We used the database to search for relevant and cutting-edge documents, and then filtered and selected them based on the content. The appropriate articles were analyzed and classified, and finally, the article was written according to the topics.The phenomenon of Trk protein fusion and its relation to tumors are described, followed by an explanation of the composition and signaling pathways of Trk kinases. The representative Trk inhibitors and the development of novel Trk inhibitors are classified according to whether they overcome drug resistance problems.This paper provides a theoretical reference for the development of novel inhibitors by introducing and summarizing the representative and novel Trk inhibitors that break through the drug resistance problem.

Two series of substituted thieno[3,2- d ]pyrimidine derivatives as EZH2 inhibitors were synthesized via structural modifications of tazemetostat.

This paper provides a theoretical reference for the development of novel inhibitors by introducing and summarizing the representative and novel Trk inhibitors that break through the drug resistance problem.

Tafasitamab(Tafasitamab-cxix;MONJUVI)是一种针对CD19的Fc工程化IgG1的抗体,通常与来那度胺联合使用.它主要用于治疗B细胞恶性肿瘤——复发或难治性弥漫大B细胞淋巴瘤(r/r DLBCL)和慢性淋巴细胞白血病(CLL),还包括由低级淋巴瘤引起的r/r DLBCL.这种药物还被用于包括滤泡性淋巴瘤和非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)在内的多种B细胞恶性肿瘤治疗的临床研究.2020年7月美国食品药品监督管理局(FDA)批准了Tafasitamab上市,这是美国批准的第一个作为该群体二线治疗的药物.本文主要就Tafasitamab的临床药理学、临床研究、不良反应概况和用药注意事项等进行了介绍.

On the basis of N-(3-amino-4-methoxyphenyl)acrylamide scaffold, a series of novel compounds containing 3-substitutional-1-methyl-1H-indole, 2-substitutional pyrrole or thiophene moieties were synthesized and their in vitro antiproliferation activities against A549 and H1975 cell lines were evaluated. The results indicated that most of the compounds showed moderate to excellent antitumor activities. Especially, compounds 9a (A549 IC50 = 1.96 mu M, H1975 IC50 = 0.095 mu M), 17i (A549 IC50 = 4.17 mu M, H1975 IC50 = 0.052 mu M), 17j (A549 IC50 = 1.67 mu M, H1975 IC50 = 0.061 mu M) exhibited comparable antitumor activities and selectivity ratios compared to the positive control osimertinib (A549 IC50 = 2.91 mu M, H1975 IC50 = 0.064 mu M). In vitro inhibitory activities against EGFR kinases containing different mutations were also tested. Compound 17i showed remarkable inhibitory activity (with IC50 value of 1.7 nM) to EGFR(L858R/T790M) kinase and selectivity (22-folds compared to EGFRWT kinase). Furthermore, acridine orange/ethidium bromide (AO/EB) staining assay, cell apoptosis assay, cell cycle distribution assay and wound-healing assay of the compounds 9a and 17i were performed on H1975 cell line. The results showed dose-dependent activities of the induction of apoptosis, G0/G1-phase arrestation and inhibition of migration, which were similar to the positive control osimertinib. Additionally, molecular docking analysis was performed to seek the possible binding mode between the selected compounds (9a, 17i-17j) and EGFR(L858R/T790M) kinase. The results demonstrated that compound 17i is a promising candidate and worth further study.

Aim: An active-passive dual-targeting gambogic acid HPMA Copolymer Coupling drug system with high efficiency, low toxicity and high selectivity was constructed. Methods: The gambogic acid HPMA copolymer coupling drug system was constructed and its structure was characterized. The cytotoxicity of gambogic acid HPMA copolymer was detected by MTT assay. The pharmacokinetics of gambogic acid HPMA copolymer was evaluated in mice. Targetability of gambogic acid HPMA copolymer was evaluated by tissue distribution experiment. The in vitro antitumor activity of gambogic acid HPMA copolymer was evaluated by pharmacodynamics experiment in mice. Results: Two copolymers of gambogic acid HPMA were successfully prepared. The copolymers showed reduced cytotoxicity and a certain sustained release effect and targeting property.In vivo pharmacodynamic experiments also showed better anti-tumor effects than GA. Discussion: In this study, gambogic acid was combined with HPMA polymer and the targeting molecule D-galactose/folic acid to form a polymer micelle with high efficiency, low toxicity and high selectivity for active-passive dual targeting. The construction of the drug system provides new ideas for future formulation research and development.

Background: Malignant tumor is a disease that seriously threatens human health. At present, more and more research results show that the pathogenesis of different tumors is very complicated, and the methods of clinical treatment are also diverse. This review analyzes and summarizes the role of fat mass and obesity associated (FTO) gene in different tumors, and provides a reference value for research and drug treatment methods. Methods: We conducted a comprehensive literature search using the database. According to the main purpose of the article, irrelevant articles were excluded from the research summary and included in the relevant articles. Finally, the relevant information of the article was summarized. Result: In this article, the relationship between malignant tumors and FTO is introduced by citing many documents. In addition, the inhibitors that act on FTO are listed. Conclusion: This article has shown that FTO protein is a demethylase that can regulate N6-methyladenosine (m6A) levels in mRNA and plays a key role in the progression and resistance of various tumors such as leukemia, breast cancer, and lung cancer.