Small-molecule modulators of tumor immune microenvironment.

In recent years, tumor immunotherapy, aimed at increasing the activity of immune cells and reducing immunosuppressive effects, has attracted wide attention. Among them, immune checkpoint blocking (ICB) is the most commonly explored therapeutic approach. All approved immune checkpoint inhibitors (ICIs) are clinically effective monoclonal antibodies (mAbs). Compared with biological agents, small-molecule drugs have many unique advantages in tumor immunotherapy. Therefore, they also play an important role. Immunosuppressive signals such as PD-L1, IDO1, and TGF-ß, etc. overexpressed in tumor cells form the tumor immunosuppressive microenvironment. In addition, the efficacy of multi-pathway combined immunotherapy has also been reported and verified. Here, we mainly reviewed the mechanism of tumor immunotherapy, analyzed the research status of small-molecule modulators, and discussed drug candidates' structure-activity relationship (SAR). It provides more opportunities for further research to design more immune small-molecule modulators with novel structures.

pH regulators and their inhibitors in tumor microenvironment.

As an important characteristic of tumor, acidic tumor microenvironment (TME) is closely related to immune escape, invasion, migration and drug resistance of tumor. The acidity of the TME mainly comes from the acidic products produced by the high level of tumor metabolism, such as lactic acid and carbon dioxide. pH regulators such as monocarboxylate transporters (MCTs), carbonic anhydrase IX (CA IX), and Na+/H+ exchange 1 (NHE1) expel protons directly or indirectly from the tumor to maintain the pH balance of tumor cells and create an acidic TME. We review the functions of several pH regulators involved in the construction of acidic TME, the structure and structure-activity relationship of pH regulator inhibitors, and provide strategies for the development of small-molecule antitumor inhibitors based on these targets.

Recent advances in pyruvate dehydrogenase kinase inhibitors: Structures, inhibitory mechanisms and biological activities.

Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.

The Progress of Small Molecule Targeting BCR-ABL in the Treatment of Chronic Myeloid Leukemia.

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease. According to the American Cancer Society's 2021 cancer data report, new cases of CML account for about 15% of all leukemias. CML is generally divided into three stages: chronic phase, accelerated phase, and blast phase. Nearly 90% of patients are diagnosed as a chronic phase. Allogeneic stem cell transplantation and chemotherapeutic drugs, such as interferon IFN-α were used as the earliest treatments for CML. However, they could generate obvious side effects, and scientists had to seek new treatments for CML. A new era of targeted therapy for CML began with the introduction of imatinib, the first-generation BCR-ABL kinase inhibitor. However, the ensuing drug resistance and mutant strains led by T315I limited the further use of imatinib. With the continuous advancement of research, tyrosine kinase inhibitors (TKI) and BCR-ABL protein degraders with novel structures and therapeutic mechanisms have been discovered. From biological macromolecules to classical target protein inhibitors, a growing number of compounds are being developed to treat chronic myelogenous leukemia. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in CML therapy, including TKIs and BCR-ABL protein degrader. The examples provided herein describe the pharmacology activity of small-molecule drugs. These drugs will provide new enlightenment for future treatment directions.

Research and development of N,N'-diarylureas as anti-tumor agents.

Tumor neovascularization provides abundant nutrients for the occurrence and development of tumors, and is also an important factor in tumor invasion and metastasis, which has attracted extensive attention in anti-tumor therapy. Sorafenib is a clinically approved multi-targeted anti-tumor drug that targets vascular endothelial growth factor receptor (VEGFR) and inhibits the formation of tumor angiogenesis, thereby achieving the purpose of suppressing tumor growth. Since the approval of sorafenib, N,N'-diarylureas have received extensive attention as the key pharmacophore in its chemical structure. And a series of N,N'-diarylureas were designed and synthesized to screen a new generation of anti-tumor drug candidates through chemical modification and structural optimization. Moreover, the rational design of targeted drugs is beneficial to reduce toxic side effects and drug resistance and improve the curative effect. Here, this article reviews the research progress in the design, classification, structure-activity relationship (SAR) and biological activity of N,N'-diarylureas, in order to provide some prospective routes for the development of clinically effective anti-tumor drugs.

Synthesis and anti-hepatocellular carcinoma evaluation of salicylic acid-modified indole trimethoxy flavonoid derivatives.

Simultaneous inhibition of tumor vasculature and the glycolysis pathway may be a targeted anti-tumor strategy to inhibit tumor nutrient supply. Flavonoids are natural products with strong biological activity, which inhibit hypoxia induction factor 1α (HIF-1α) regulating glycolysis and tumor angiogenesis, while salicylic acid can reduce the glycolysis level of tumor cells by inhibiting related rate-limiting enzymes. A series of salicylic acid-modified indole trimethoxy-flavone derivatives were designed and synthesized by introducing benzotrimethoxy-structure commonly used in blood vessel blockers, and their anti-tumor activities were evaluated. Among them, compound 8f exhibited significant anti-proliferative activity against two hepatoma cells, HepG-2 and SMMC-7721, with IC50 values of 4.63 ± 1.13 µM and 3.11 ± 0.35 µM, respectively. Colony formation experiments also further verified its excellent in vitro anti-tumor activity. In addition, compound 8f showed the ability to induce apoptosis in SMMC-7721 cells in a concentration-dependent manner. After treatment with compound 8f, the expressions of the rate-limiting enzymes PKM2, PFKM, HK2 and tumor angiogenesis-related vascular endothelial growth factor of the glycolytic pathway were all down-regulated, and the lactate level in the hepatoma cell SMMC-7721 was significantly reduced. The morphology of the nucleus and tubulin was also observed to disperse gradually with the increase of compound 8f concentration. And compound 8f showed strong binding ability to tubulin. Our results suggest that the strategy of synthesizing the salicylic acid-modified indole flavone derivative 8f is a way to obtain active anti-tumor candidate compounds that may be further developed as targeted agents to inhibit tumor vasculature and glycolytic pathways.

Advances in antitumor research of HIF-1α inhibitor YC-1 and its derivatives.

Generally, hypoxia-inducible factor-1α (HIF-1α) is highly expressed in solid tumors, it plays a key role in the occurrence and development of tumors, hindering cancer treatment in various ways. The antitumor activity and pharmacological mechanism of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1­benzyl indazole], an HIF-1α inhibitor, and the design and synthesis of its derivatives have attracted tremendous attention in the field of antitumor research. YC-1 is a potential drug candidate and a lead compound for tumor therapy. Hence, the multifaceted mechanism of action of YC-1 and the structure activity relationship (SAR) of its derivatives are important factors to be considered for the development of HIF-1α inhibitors. Therefore, this review aimed to provide a comprehensive overview of the various antitumor mechanisms of YC-1 in antitumor research and an in-depth summary of the SAR for the development of its derivatives. A full understanding and discussion of these aspects are expected to provide potential ideas for developing novel HIF-1α inhibitors and antitumor drugs belonging to the YC-1 class. The review also highlighted the application prospects of the YC-1 class of potential antitumor candidates, and provided some unique insights about these antitumor agents.

Design, synthesis, and antitumor evaluation of trimethoxyflavonoid with arylurea structure against hepatocellular carcinoma.

Simultaneous targeting of tumor vasculature and inhibitors of tumor cell glycolysis may be a promising antitumor strategy. Here, we reported the total synthesis and biological evaluation of A-ring arylurea flavonoid derivatives with B-ring trimethoxy group, which exhibited potent antitumor activity against a variety of tumor cells in vitro. Most of the derivatives showed in vitro antitumor activity on HepG-2, HGC-27, MDA-MB-231, and A549 cells. Among them, compounds 8e, 8f, 8g, 8h, 8j, and 8l also exhibited significant anti-proliferation effects on liver tumor cell subtypes BEL-7402 and SMMC-7721. Compound 8l had the lowest IC50 value (5.61 ± 0.39 µM) on HepG-2 cells, and showed the effects of inhibiting colony formation, arresting the cell cycle in G0 /G1 phase, and inducing apoptosis in a concentration-dependent manner. In addition, the toxicity of compound 8l on human normal cells LO2 and GES-1 was lower than that of sorafenib. The inhibitory effects of compound 8l on the expression of glycolytic rate-limiting enzymes HKII, PFK-1, PKM2 and vascular endothelial growth factor were further evaluated. Corresponding reduction in intracellular lactate was also detected after compound 8 treatment. Our results support an antitumor strategy targeting tumor vasculature and glycolysis to discover and develop a new generation of antitumor drugs.

Recent Advances of Curcumin Derivatives in Breast Cancer.

Curcumin is a potential plant-derived drug for the treatment of breast cancer. Poor solubility and bioavailability are the main factors that limit its clinical application. Various structural modification strategies have been developed to improve the anti-breast cancer activity of curcumin. This review focuses on the difference of modification sites and heterocyclic/non-heterocyclic modifications to systematically summarize curcumin derivatives with better anti-breast cancer activity.

Withdrawal: Advances in Development of Drugs for Chronic Myelogenous Leukemia

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Recent Progress in the Research on Benzimidazole PARP-1 Inhibitors.

Poly (ADP-ribose) polymerase-1 (PARP-1) is a multifunctional protein that plays an important role in DNA repair and genome integrity. PARP-1 inhibitors can be used as effective drugs not only to treat BRCA-1/2 deficient cancers because of the synthetic lethality effect but also to treat non- BRCA1/2 deficient tumours because of the effect of PARP capture. Therefore, PARP inhibitors have become a focus of compelling research. Among these inhibitors, substituted benzimidazole derivatives were mainly concerned as lead compounds. However, the commercially available benzimidazole PARP-1 inhibitors have some shortcomings, such as serious toxicity in combination with chemotherapy drugs and in vivo cardiovascular side effects such as anemia. Therefore it is crucial for scientists to explore more structure-activity relationships of the benzimidazole PARP-1 inhibitors and access safer and more effective PARP inhibitors. As the binding regions of PARP-1 and the substrates are usually characterized by NI site and AD site, the modification of benzimidazoles mainly occurs on the benzimidazole skeleton (NI site) and the side chain of benzimidazole in the 2-C position (AD site). Herein, the recent progress in the research on benzamides PARP inhibitors was introduced. We noticed that even though many efforts were made to the modification of NI sites, there was still a lack of optimistic and impressive results. However, the structure-activity relationships of the modification of AD sites have not been thoroughly discovered yet. We hope that enlightened by the previous research, more research on AD sites should be carried out, and more effective benzimidazole PARP-1 inhibitors could be designed, synthesized, and applied to clinics.

Recent progress of research on anti-tumor agents using benzimidazole as the structure unit.

With the development of exploration for disease-related proteins or receptors, more and more novel structural lead compounds are required to designed and synthesized. The benzimidazole is an effective structural unit in which the benzene ring is fused at the 4 and 5 positions of the imidazole ring and wildly used in drug design. Here, we introduce some recent progress of research for anti-tumor agents which was target to various target proteins such as DNA topoisomerase, angiogenesis, serine/threonine protein kinase, and tyrosine protein kinase. These anti-tumor agents are all introduced benzimidazole as the structure unit. Further docking study showed that the benzimidazole group was not only act as a skeleton to expand the structure of molecule but also as an excellent ligand unit to form hydrogen bond or π-π conjugation and hydrophobic interaction with target proteins or receptors. We expect that introducing benzimidazole in the chemical structure could be a reasonable and priority strategy in novel anti-tumor agents' design.

Synthesis and evaluation of 2-(4-[4-acetylpiperazine-1-carbonyl] phenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives as potential PARP-1 inhibitors and preliminary study on structure-activity relationship.

Although 1H-benzo[d]imidazole-4-carboxamide derivatives have been explored for a long time, the structure-activity relationship of the substituents in the hydrophobic pocket (AD binding sites) has not thoroughly discovered. Here in, a series of 2-(4-[4-acetylpiperazine-1-carbonyl]phenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives have been designed, synthesized, and successful characterization as novel and effective poly ADP-ribose polymerases (PARP)-1 inhibitors to improve the structure-activity relationships about the substituents in the hydrophobic pocket. These derivatives were evaluated for their PARP-1 inhibitory activity and cellular inhibitory against BRCA-1 deficient cells (MDA-MB-436) and wild cells (MCF-7) using PARP kit assay and MTT method. The results indicated that compared with other heterocyclic compounds, furan ring-substituted derivatives 14n-14q showed better PARP-1 inhibitory activity. Among this derivatives, compound 14p displayed the strongest inhibitory effects on PARP-1 enzyme (IC50  = 0.023 µM), which was close to that of Olaparib. 14p (IC50  = 43.56 ± 0.69 µM) and 14q (IC50  = 36.69 ± 0.83 µM) displayed good antiproliferation activity on MDA-MB-436 cells and inactivity on MCF-7 cells, indicating that 14p and 14q have high selectivity and targeting. The molecular docking method was used to explore the binding mode of compound 14p and PARP-1, and implied that the formation of hydrogen bond was essential for PARP-1 inhibition activities. This study also showed that in the hydrophobic pocket (AD binding sites), the introduction of strong electronegative groups (furan ring, e.g.) or halogen atoms in the side chain of benzimidazole might improve its inhibitory activity and this strategy could be applied in further research.

Discovery and development of tumor glycolysis rate-limiting enzyme inhibitors.

Tumor cells mainly provide necessary energy and substances for rapid cell growth through aerobic perglycolysis rather than oxidative phosphorylation. This phenomenon is called the "Warburg effect". The mechanism of glycolysis in tumor cells is more complicated, which is caused by the comprehensive regulation of multiple factors. Abnormal enzyme metabolism is one of the main influencing factors and inhibiting the three main rate-limiting enzymes in glycolysis is thought to be important strategy for cancer treatment. Therefore, numerous inhibitors of glycolysis rate-limiting enzyme have been developed in recent years, such as the latest HKII inhibitor and PKM2 inhibitor Pachymic acid (PA) and N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide. The review focuses on source, structure-activity relationship, bioecological activity and mechanism of the three main rate-limiting enzymes inhibitors, and hopes to guide the future research on the design and synthesis of rate-limiting enzyme inhibitors.

Clinical crosstalk between microRNAs and gastric cancer (Review).

Globally, there were over 1 million new gastric cancer (GC) patients in 2018 and GC has become the sixth most common cancer worldwide. GC caused 783,000 deaths worldwide in 2018, making it the third most deadly cancer type. miRNAs are short (~22 nucleotides in length) non­coding RNA molecules, which can regulate gene expression passively at a post­transcriptional level. There are more and more in­depth studies on miRNAs. There are numerous conclusive evidences that there is an inseparable link between miRNAs and GC. miRNAs can affect the entire process of GC, including the oncogenesis, development, diagnosis, treatment and prognosis of GC. Although many miRNAs have been linked to GC, few can be applied to clinical practice. This review takes the clinical changes of GC as a clue and summarizes the miRNAs related to GC that have confirmed the mechanism of action in the past three years. Through in­depth study and understanding of the mechanism of those miRNAs, we predict their possible clinical uses, and suggest some new insights to overcome GC.

Design, synthesis, and biological evaluation of 3',4',5'-trimethoxy evodiamine derivatives as potential antitumor agents.

A series of compounds bearing 3',4',5'-trimethoxy module into the core structure of evodiamine were designed and synthesized. The synthesized compounds were screened in vitro for their antitumor potential. MTT results showed that compounds 14a-14c and 14i-14j had significant effects, with compound 14h being the most prominent, with an IC50 value of 3.3 ± 1.5 µM, which was lower than evodiamine and 5-Fu. Subsequent experiments further confirmed that compound 14h could inhibit cell proliferation and migration, and induce G2/M phase arrest to inhibit the proliferation of HGC-27 cells, which is consistent with the results of the cytotoxicity experiment. Besides, 14h could inhibit microtubule assembly and might kill tumor cells by inhibiting VEGF and glycolysis. All experimental results indicate that compound 14h might be a potential drug candidate for the treatment of gastric cancer and was worthy of further study.

A novel salvianolic acid A analog with resveratrol structure and its antioxidant activities in vitro and in vivo.

E-DRS is a novel salvianolic acid A (SAA) analog, which was synthesized from resveratrol (RES) and methyldopate. Its structure is similar to that of SAA, but the 3',4'-dihydroxy-trans-stilbene group and the ester structure in SAA were replaced by the RES structure and an amine group, respectively. E-DRS scavenged free oxygen radicals effectively, including superoxide anion (ascorbic acid > E-DRS > SAA ≥ rutin > RES) and DPPH radical (rutin > E-DRS ≥ ascorbic acid > SAA > RES), and exhibited powerful total antioxidant capacity (ascorbic acid > E-DRS > SAA ≥ rutin > RES) in vitro. Furthermore, oral administration of E-DRS dose-dependently and significantly decreased CCl4 -induced oxidative stress in mice as indicated by the decreased content of hepatic malondialdehyde (MDA). In addition, oral administration of E-DRS also increased the content of nonenzymatic antioxidant glutathione (GSH) and the activity of antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) in the liver of mice. All these results demonstrated that E-DRS had good antioxidant activities both in vitro and in vivo, and could be a potential antioxidant agent after further optimization and evaluation.

Recent advances in Bcr-Abl tyrosine kinase inhibitors for overriding T315I mutation.

BCR-ABL is a gene produced by the fusion of the bcr gene and the c-abl proto-oncogene and is considered to be the main cause of chronic myelogenous leukemia (CML) production. Therefore, the development of selective Bcr-Abl kinase inhibitors is an attractive strategy for the treatment of CML. However, in the treatment of CML with a Bcr-Abl kinase inhibitor, the T315I gatekeeper mutant disrupts the important contact interaction between the inhibitor and the enzyme, resistant to the first- and second-generation drugs currently approved, such as imatinib, bosutinib, nilotinib, and dasatinib. In order to overcome this special resistance, several different strategies have been explored, and many molecules have been studied to effectively inhibit Bcr-Abl T315I. Some of these molecules are still under development, and some are being studied preclinically, and still others are in clinical research. Herein, this review reports some of the major examples of third-generation Bcr-Abl inhibitors against the T315I mutation.

FB-15 inhibits MGC-803 cells growth by regulating energy metabolism.

In this study, we scrutinized the anticancer effects of FB-15 on human gastric carcinoma MGC-803 cells in vitro and vivo, and its preliminary effect on tubulin and HIF-1α. We confirmed that FB-15 not only inhibited the proliferation of a large number of cells in a concentration and time-dependent manner but also inhibited proliferation of a single cell to form clones. FB-15 manifested little cytotoxicity for normal stomach cells GES-1. The flow cytometry analysis displayed that FB-15 induced apoptosis MGC-803 cells and mainly arrested cells in the S phase in a concentration-dependent manner. The results of the wound healing assay indicated that FB-15 suppressed cell migration. Furthermore, the western blotting showed that FB-15 down-regulated the expression of ß3-tubulin and HIF-1α, consistent with Immunohistochemical assay. The binding modes of FB-15 with tubulin were clarified by molecular docking. FB-15 significantly suppressed the growth of MGC-803 gastric cancer tumors. The inhibitory effect of FB-15 on tumor growth was superior to 5-Fu. Taken together, these results provided evidence for FB-15 to be used as an effective anticancer drug candidate for gastric cancer.

Synthesis and biological evaluation of novel 5,6,7-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents.

5,6,7-Trimethoxy flavonoid salicylate derivatives were designed by the joining of three important pharmacophores (TMP, flavonoid, and SA) according to the combination principle. A series of novel trimethoxy flavonoid salicylate derivatives were synthesized and their in vitro anti-tumor activities were evaluated. Among these derivatives, compound 7f exhibited excellent antiproliferative activity against HGC-27 cells and MGC-803 cells with IC50 values of 10.26 ± 6.94 µM and 17.17 ± 3.03 µM, respectively. Subsequently, the effects on cell colony formation (clonogenic survival assay), cell migration (wound healing assay), cell cycle distribution (PI staining assay), cell apoptosis (Hoechst 33258 staining assay and annexin V-FITC/PI dual staining assay), lactate level (lactate measurement), microtubules disarrangement (immunofluorescence staining analysis) and docking posture (molecular docking simulation) were determined. Further western blot analysis confirmed that compound 7f could effectively down-regulate the expression of glycolysis-related proteins HIF-1α, PFKM and PKM2 and tumor angiogenesis-related proteins VEGF. Overall, these studies suggested that compound 7f, as the representative compound of those, might be a promising candidate for the treatment of gastric cancer and deserved the further studies.